Monofluoroalkyl derivatives

ABSTRACT

The present invention provides certain monofluoroalkyl derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.

This is a 371 of PCT/US00/08734 filed Apr. 17, 2000 which claimspriority to U.S. Provisional Application No. 60/177,566 filed Jan. 21,2000 and U.S. Provisional Application No. 60/131,771 filed Apr. 30,1999.

The present invention relates to the potentiation of glutamate receptorfunction using certain monofluoroalkyl derivatives. It also relates tonovel monofluoroalkyl derivatives, to processes for their preparationand to pharmaceutical compositions containing them.

In the mammalian central nervous system (CNS), the transmission of nerveimpulses is controlled by the interaction between a neurotransmitter,that is released by a sending neuron, and a surface receptor on areceiving neuron, which causes excitation of this receiving neuron.L-Glutamate, which is the most abundant neurotransmitter in the CNS,mediates the major excitatory pathway in mammals, and is referred to asan excitatory amino acid (EAA). The receptors that respond to glutamateare called excitatory amino acid receptors (EAA receptors). See Watkins& Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan,Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989);Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25(1990). The excitatory amino acids are of great physiologicalimportance, playing a role in a variety of physiological processes, suchas long-term potentiation (learning and memory), the development ofsynaptic plasticity, motor control, respiration, cardiovascularregulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types.Receptors that are directly coupled to the opening of cation channels inthe cell membrane of the neurons are termed “ionotropic”. This type ofreceptor has been subdivided into at least three subtypes, which aredefined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), andkainic acid (KA). The second general type of receptor is the G-proteinor second messenger-linked “metabotropic” excitatory amino acidreceptor. This second type is coupled to multiple second messengersystems that lead to enhanced phosphoinositide hydrolysis, activation ofphospholipase D, increases or decreases in c-AMP formation, and changesin ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci.,14, 13 (1993). Both types of receptors appear not only to mediate normalsynaptic transmission along excitatory pathways, but also participate inthe modification of synaptic connections during development andthroughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol.Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41 (1990).

AMPA receptors are assembled from four protein sub-units known as GluR1to GluR4, while kainic acid receptors are assembled from the sub-unitsGluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, MolecularPharmacology 44: 505–510, 1993. It is not yet known how these sub-unitsare combined in the natural state. However, the structures of certainhuman variants of each sub-unit have been elucidated, and cell linesexpressing individual sub-unit variants have been cloned andincorporated into test systems designed to identify compounds which bindto or interact with them, and hence which may modulate their function.Thus, European patent application, publication number EP-A2-0574257discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B.European patent application, publication number EP-A1-0583917 disclosesthe human sub-unit variant GluR4B.

One distinctive property of AMPA and kainic acid receptors is theirrapid deactivation and desensitization to glutamate. Yamada and Tang,The Journal of Neuroscience, September 1993, 13(9): 3904–3915 andKathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634–6647. Thephysiological implications of rapid desensitization, and deactivation ifany, are not fully understood.

It is known that the rapid desensitization and deactivation of AMPAand/or kainic acid receptors to glutamate may be inhibited using certaincompounds. This action of these compounds is often referred to in thealternative as “potentiation” of the receptors. One such compound, whichselectively potentiates AMPA receptor function, is cyclothiazide. Partinet al., Neuron. Vol. 11, 1069–1082, 1993. Compounds which potentiateAMPA receptors, like cyclothiazide, are often referred to as ampakines.

International Patent Application Publication Number WO 9625926 disclosesa group of phenylthioalkylsulfonamides, S-oxides and homologs which aresaid to potentiate membrane currents induced by kainic acid and AMPA.

U.S. Pat. No. 3,143,549 discloses certain phenylalkylsulfamides,including 1-methyl-2-phenylethyl dimethylsulfamide. The compounds aresaid to have central nervous system activity, in particular antianxietyand tranquilizing properties.

U.S. Pat. No. 3,267,139 discloses certainN′-trimethylacetyl-N-phenylalkylsulfamides and-phenylcyclopropylsulfamides having central nervous system activity andanticonvulsant activity. The compounds are also said to produceParkinson-like symptoms in experimental animals.

U.S. Pat. No. 3,860,723 discloses a method of increasing feed intake ofhealthy animals using certain phenylalkylsulfamides.

Foye et al., J. Pharm. Sci. (1971), 60(7), 1095–6 discloses certainphenylalkyl methylsulfonamides including N-1-methyl-2-phenylethylmethanesulfonamide, having hypotensive activity.

British Patent Specification Number 1,059,360 discloses certainphenylalkylsulfamides having activity as sedatives, narcotics andanticonvulsants, including1-(1-methyl-2-phenylethylaminosulphonyl)piperidine.

U.S. Pat. No. 4,210,749 discloses N-1-methyl-2-phenyl-3-methoxy ethylbutane-sulfonamide.

Gualtieri et al., J. Pharm. Sci., (1973), 62(5), 849–851 disclosesN-1-methyl-2-phenylethyl butanesulfonamide and its evaluation as amosquito repellent.

Foye et al., J. Pharm. Sci. (1979), 68(5), 591–5 disclosesN-1-methyl-2-(4-chlorophenyl)ethyl methane-sulfonamide.

Foye and Sane, J. Pharm. Sci. (1977), 66(7), 923–6 disclosesN-methanesulfonyl and N-trifluoromethanesulfonyl derivatives ofamphetamines and certain 4-substituted analogs thereof, and theirevaluation for central nervous system and anorexic effects.

European patent application publication no. EP-A1-0657442 disclosescertain naphthyloxyacetic acid derivatives as PEG2 agonists andantagonists. N-(2,2-diphenylethyl)-methanesulfonamide is disclosed as anintermediate at page 53, line 38.

U.S. Pat. No. 3,629,332 discloses certain N-aryl- and N-heteroarylalkylfluoroalkane sulfonamides as plant growth modifiers, includingN-(alpha-methylphenylethyl) trifluoromethanesulfonamide,difluoromethanesulfonamide and fluoromethanesulfonamide. Some of thecompounds are also said to have other biological activity, includinginsecticidal, acaricidal, nematicidal, analgesic and anti-inflammatoryactivity.

Ampakines have been shown to improve memory in a variety of animaltests. Staubli et al., Proc. Natl. Acad. Sci., Vol. 91, pp 777–781,1994, Neurobiology, and Arai et al., The Journal of Pharmacology andExperimental Therapeutics, 278: 627–638, 1996.

In addition, certain sulfonamide derivatives which potentiate glutamatereceptor function in a mammal have been disclosed in InternationalPatent Application Publication WO 98/33496 published Aug. 6, 1998 andInternational Patent Application Publication WO 99/43285 published Sep.2, 1999.

The present invention provides compounds of formula I:

wherein:

-   -   A represents SO₂, CO₂, or CONH;    -   R^(a) represents (1–6C)alkyl, (2–6C)alkenyl,        —(1–4C)alkyl(3–8C)cycloalkyl, or —(1–4C)alkylaromatic;    -   R^(b) represents H, (1–6C)alkyl, (2–6C)alkenyl,        —(1–4C)alkyl(3–8C)cycloalkyl, or —(1–4C)alkylaromatic; or    -   R^(a) and R^(b) together with the carbon atoms to which they are        attached form a (3–8C) saturated carbocyclic ring, a (3–8C)        saturated carbocyclic ring containing a heteroatom selected from        the group consisting of sulfur or oxygen, or a (5–8C)        carbocyclic ring containing one double bond;    -   R¹ represents an unsubstituted or substituted aromatic group, an        unsubstituted or substituted heteroaromatic group, or an        unsubstituted or substituted (5–8C)cycloalkyl group;    -   R² represents (1–6C)alkyl, (3–6C)cycloalkyl, (1–6C)fluoroalkyl,        (1–6C)chloroalkyl, (2–6C)alkenyl, (1–4C)alkoxy(1–4C)alkyl,        phenyl which is unsubstituted or substituted by halogen,        (1–4C)alkyl or (1–4C)alkoxy, or when A represents SO₂, a group        of formula R³R⁴N in which R³ and R⁴ each independently        represents (1–4C)alkyl or, together with the nitrogen atom to        which they are attached form an azetidinyl, pyrrolidinyl,        piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or        octahydroazocinyl group;    -   or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of potentiatingglutamate receptor function in a patient, which comprises administeringto said patient an effective amount of a compound of formula I.

The present invention provides a method of treating cognitive disordersin a patient, which comprises administering to said patient an effectiveamount of a compound of formula I.

In addition, the present invention further provides a method of treatingcognitive deficits associated with psychosis in a patient, whichcomprises administering to said patient an effective amount of acompound of formula I.

According to another aspect, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt thereof forthe manufacture of a medicament for potentiating glutamate receptorfunction.

In addition, the present invention provides the use of a compound offormula I or a pharmaceutically acceptable salt thereof for potentiatingglutamate receptor function.

The invention further provides pharmaceutical compositions comprising, acompound of formula I and a pharmaceutically acceptable diluent orcarrier.

The present invention further includes compounds of the formula:

wherein

-   -   R^(a) represents (1–6C)alkyl, (2–6C)alkenyl,        —(1–4C)alkyl(3–8C)cycloalkyl, or —(1–4C)alkylaromatic;    -   R^(b) represents H, (1–6C)alkyl, (2–6C)alkenyl,        —(1–4C)alkyl(3–8C)cycloalkyl, or —(1–4C)alkylaromatic; or    -   R^(a) and R^(b) together with the carbon atoms to which they are        attached form a (3–8C) saturated carbocyclic ring, a (3–8C)        saturated carbocyclic ring containing a heteroatom selected from        the group consisting of sulfur or oxygen, or a (5–8C)        carbocyclic ring containing one double bond;    -   R¹ represents an unsubstituted or substituted aromatic group, an        unsubstituted or substituted heteroaromatic group, or an        unsubstituted or substituted (5–8C)cycloalkyl group;    -   or a pharmaceutically acceptable salt thereof;        with the proviso that when R^(a) is methyl, then R¹ is other        than 4-bromophenyl.

This invention also encompasses novel intermediates, and processes forthe synthesis of the compounds of formula I.

In this specification, the term “potentiating glutamate receptorfunction” refers to any increased responsiveness of glutamate receptors,for example AMPA receptors, to glutamate or an agonist, and includes butis not limited to inhibition of rapid desensitization or deactivation ofAMPA receptors to glutamate.

A wide variety of conditions may be treated or prevented by thecompounds of formula I and their pharmaceutically acceptable saltsthrough their action as potentiators of glutamate receptor function.Such conditions include those associated with glutamate hypofunction,such as psychiatric and neurological disorders, for example cognitivedisorders; neuro-degenerative disorders such as Alzheimer's disease;age-related dementias; age-induced memory impairment; movement disorderssuch as tardive dyskinesia, Hungtington's chorea, myoclonus andParkinson's disease; reversal of drug-induced states (such as cocaine,amphetamines, alcohol-induced states); depression; attention deficitdisorder; attention deficit hyperactivity disorder; psychosis; cognitivedeficits associated with psychosis, drug-induced psychosis, and sexualdysfunction. The compounds of formula I may also be useful for improvingmemory (both short term and long term) and learning ability. The presentinvention provides the use of compounds of formula I for the treatmentof each of these conditions.

It is understood that compounds of the formulas Ia′, Ib′, Ic′, and In′;

wherein R¹ represents an unsubstituted or substituted aromatic group, anunsubstituted or substituted heteroaromatic group, or an unsubstitutedor substituted (5–8C)cycloalkyl group; or a pharmaceutically acceptablesalt thereof; are included within the scope of formula I.

The present invention includes the pharmaceutically acceptable salts ofthe compounds defined by formula I. A compound of this invention canpossess a sufficiently acidic group, a sufficiently basic group, or bothfunctional groups, and accordingly react with any of a number of organicand inorganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. The term “pharmaceutically acceptablesalt” as used herein, refers to salts of the compounds of the aboveformula which are substantially non-toxic to living organisms. Typicalpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with apharmaceutically acceptable mineral or organic acid or an organic orinorganic base. Such salts are known as acid addition and base additionsalts. Such salts include the pharmaceutically acceptable salts listedin Journal of Pharmaceutical Science, 66, 2–19 (1977) which are known tothe skilled artisan. Acids commonly employed to form acid addition saltsare inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, phosphoric acid, and the like, andorganic acids such as p-toluenesulfonic, methanesulfonic acid,benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonicacid, succinic acid, citric acid, benzoic acid, acetic acid, and thelike. Examples of such pharmaceutically acceptable salts are thesulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate,caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride,isobutyrate, caproate, heptanoate, propiolate, propionate,phenylpropionate, salicylate, oxalate, malonate, succinate, suberate,sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate,nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate,teraphthalate, butyne-1,4-dioate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxybenzoate, naphthalene-2-benzoate, phthalate,p-toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate,xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate,phenylbutyrate, citrate, lactate, α-hydroxybutyrate, glycolate,tartrate, benzenesulfonate, methanesulfonate, ethanesulfonate,propanesulfonate, hydroxyethanesulfonate, 1-naphthalenesulfonate,2-napththalenesulfonate, 1,5-naphthalenedisulfonate, mandelate,tartarate, and the like. Preferred pharmaceutically acceptable acidaddition salts are those formed with mineral acids such as hydrochloricacid and hydrobromic acid, and those formed with organic acids such asmaleic acid, oxalic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that the above salts may form hydratesor exist in a substantially anhydrous form.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation:

${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the specific stereoisomersand enantiomers of compounds of formula I can be prepared by one ofordinary skill in the art utilizing well known techniques and processes,such as those disclosed by J. Jacques, et al., “Enantiomers, Racemates,and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel andS. H. Wilen, “Stereochemistry of Organic Compounds”, (Wiley-Interscience1994), and European Patent Application No. EP-A-838448, published Apr.29, 1998. Examples of resolutions include recrystallization techniquesor chiral chromatography.

Some of the compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103–120.

As used herein, the term “aromatic group” means the same as aryl, andincludes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and thelike.

The term “heteroaromatic group” includes an aromatic 5–6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen, and a bicyclic group consisting of a 5–6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen fused with a benzene ring or another 5–6 membered ringcontaining one to four atoms selected from oxygen, sulfur and nitrogen.Examples of heteroaromatic groups are thienyl, furyl, oxazolyl,isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl,isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, indolyl, and quinolyl.

The term “substituted” as used in the term “substituted aromatic orheteroaromatic group” herein signifies that one or more (for example oneor two) substituents may be present, said substituents being selectedfrom atoms and groups which, when present in the compound of formula I,do not prevent the compound of formula I from functioning as apotentiator of glutamate receptor function.

It is understood that when R¹ represents an unsubstituted or substituted(5–8C)cycloalkyl group, mixtures of cis and trans isomers may resultwhich can be separated into the individual cis and trans isomers by oneof ordinary skill in the art, using standard techniques and proceduressuch as reverse phase or normal phase high performance liquidchromatography or flash chromatography, with a suitable stationary phaseand a suitable eluent. Examples of suitable stationary phases are silicagel, alumina, and the like. Examples of suitable eluents are ethylacetate/hexane, ethyl acetate/toluene, methanol/dichloromethane, and thelike. Such individual cis and trans isomers are included within thescope of the present invention.

Examples of substituents which may be present in a substituted aromatic,heteroaromatic group or (5–8C)cycloalkyl group include halogen; nitro;cyano; hydroxyimino; (1–10C) alkyl; (2–10C)alkenyl; (2–10C)alkynyl;(3–8C)cycloalkyl; hydroxy(3–8C)cycloalkyl; oxo(3–8C)cycloalkyl;halo(1–10C)alkyl; (CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1to 4, X¹ represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO,OCONR¹³, R⁹ represents hydrogen, (1–10C) alkyl, (3–10C)alkenyl,(3–10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or(3–8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently representshydrogen or (1–10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together withthe nitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl or morpholino group; N-(1–4C)alkylpiperazinyl;N-phenyl(1–4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1–4C)alkoxycarbonyl dihydrothiazolyl;(1–4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1–4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1–10C) alkyl; (2–10C)alkenyl; (2–10C)alkynyl;(3–8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1–10C)alkyl; cyano(2–10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ orNR¹⁹COO, R¹⁵ represents hydrogen, (1–10C)alkyl, phenyl(1–4C)alkyl,halo(1–10C)alkyl, (1–4C)alkoxycarbonyl(1–4C)alkyl,(1–4C)alkylsulfonylamino(1–4C)alkyl,N-(1–4C)alkoxycarbonyl)(1–4C)alkylsulfonylamino(1–4C)alkyl,(3–10C)alkenyl, (3–10C)alkynyl, (3–8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1–4C)alkyl, halo(1–4C)alkyl,di(1–4C)alkylamino and (1–4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1–10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.

The term (1–10C)alkyl includes (1–8C)alkyl, (1–6C)alkyl and (1–4C)alkyl.Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

The term (2–10C)alkenyl includes (3–10C)alkenyl, (2–8C)alkenyl,(2–6C)alkenyl and (2–4C)alkenyl. Particular values are vinyl andprop-2-enyl.

The term (2–10C)alkynyl includes (3–10C)alkynyl, (2–8C)alkynyl,(2–6C)alkynyl and (3–4C)alkynyl. A particular value is prop-2-ynyl.

The term C₁–C₆ alkoxy refers to a straight or branched alkyl chainhaving from one to six carbon atoms attached to an oxygen atom. TypicalC₁–C₆ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,butoxy, t-butoxy, pentoxy and the like. The term C₁–C₆ alkoxy includeswithin its definition the term C₁–C₄ alkoxy.

The term (3–8C)cycloalkyl, as such or in the term (3–8C)cycloalkyloxy,includes monocyclic and polycyclic groups. Particular values arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andbicyclo[2.2.2]octane. The term includes (3–6C)cycloalkyl: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

As used herein the terms “integer of from 1 to 4” or “integer of from 1to 3” includes the integers 1, 2, 3, and 4, or the integers 1, 2, and 3,respectively.

The term (5–8C)cycloalkyl includes cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

The term hydroxy(3–8C)cycloalkyl includes hydroxy-cyclopentyl, such as3-hydroxycyclopentyl.

The term oxo(3–8C)cycloalkyl includes oxocyclopentyl, such as3-oxocyclopentyl.

The terms “halogen”, “Hal” or “halide” include fluorine, chlorine,bromine and iodine unless otherwise specified.

The term halo(1–10C)alkyl includes fluoro(1–10C)alkyl, such astrifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1–10C)alkyl such aschloromethyl.

The term cyano(2–10C)alkenyl includes 2-cyanoethenyl.

The term (2–4C)alkylene includes ethylene, propylene and butylene. Apreferred value is ethylene.

The term thienyl includes thien-2-yl and thien-3-yl.

The term furyl includes fur-2-yl and fur-3-yl.

The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.

The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl andisoxazol-5-yl.

The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and[1,2,4]oxadiazol-5-yl.

The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.

The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.

The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and[1,2,4]thiadiazol-5-yl.

The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl andisothiazol-5-yl.

The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl andimidazolyl-5-yl.

The term triazolyl includes [1,2,4]triazol-3-yl and [1,2,4]triazol-5-yl.

The term tetrazolyl includes tetrazol-5-yl.

The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.

The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl,pyridazin-5-yl and pyridazin-6-yl.

The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl and pyrimidin-6-yl.

The term benzofuryl includes benzofur-2-yl and benzofur-3-yl.

The term benzothienyl includes benzothien-2-yl and benzothien-3-yl.

The term benzimidazolyl includes benzimidazol-2-yl.

The term benzoxazolyl includes benzoxazol-2-yl.

The term benzothiazolyl includes benzothiazol-2-yl.

The term indolyl includes indol-2-yl and indol-3-yl.

The term quinolyl includes quinol-2-yl.

The term dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl, and the term(1–4C)alkoxycarbonyldihydrothiazolyl includes4-methoxycarbonyl-4,5-dihydrothiazol-2-yl.

The term —(1–4C)alkyl(3–8C)cycloalkyl includes the following:

The term —(1–4C)alkylaromatic includes the following:

Preferably R^(a) is methyl, ethyl, propyl, n-butyl, sec-butyl, pentyl,and hexyl with methyl being most preferred.

Preferably R^(b) is hydrogen, methyl, ethyl, propyl, n-butyl, sec-butyl,pentyl, and hexyl, with hydrogen being most preferred.

Preferably R³ and R⁴ each represent methyl.

Examples of values for R² are methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl,chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl,4-fluorophenyl, or dimethylamino. Preferably R² is ethyl, 2-propyl ordimethylamino.

Examples of values for R⁹ are hydrogen, methyl, ethyl, propyl,isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2-pyrrolidinyl, morpholino or 2-tetrahydrofuryl.

R⁹ is preferably (1–4C)alkyl, (2–4C)alkenyl, (3–6C)cycloalkyl,pyrrolidinyl, morpholino or tetrahydrofuryl.

Examples of values for R¹⁵ are hydrogen, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl,2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl,2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

X¹ preferably represents O, CO, CONH or NHCO.

z is preferably 0.

Particular values for the groups (CH₂)_(y)X¹R⁹ and (CH₂)_(z)X³R¹⁵include (1–10C)alkoxy, including (1–6C)alkoxy and (1–4C)alkoxy, such asmethoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3–10C)alkenyloxy,including (3–6C)alkenyloxy, such as prop-2-enyloxy; (3–10C)alkynyloxy,including (3–6C)alkynyloxy, such as prop-2-ynyloxy; and (1–6C)alkanoyl,such as formyl and ethanoyl.

Examples of particular values for y are 0 and 1.

Examples of particular values for z are 0, 1, 2 and 3.

L^(a) and L^(b) preferably each independently represents CH₂.

X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH orOCH₂CONH, with a bond, O, and CONH being especially preferred.

Preferably the group (CH₂)_(y)X¹R⁹ represents CHO; COCH₃, OCH₃;OCH(CH₃)₂; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl,t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropylor cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.

Preferably the group (CH₂)_(z)X³R¹⁵ represents NH₂; CH₂NH₂; (CH₂)₂NH₂;(CH₂)₃NH₂; CONH₂; CONHCH₃; CON(CH₃)₂; N(C₂H₅)₂; CH₂OH; CH(OH)CH₃;CH(OH)CH₂CH₂; CHO; COCH₃; COOH; COOCH₃; CH₂NHCOOC(CH₃)₃;(CH₂)₂NHCOOC(CH₃)₃; SO₂NH₂; NHSO₂CH₃; NHSO₂CH(CH₃)₂; a group of formula(CH₂)₂NHSO₂R¹⁵ in which R¹⁵ represents CH₃, CH₂CH₃, CH(CH₃)₂, (CH₂)₂CH₃,(CH₃)₃CH₃, benzyl, CH₂CF₃, 2-methoxycarbonylethyl, cyclohexyl,10-camphoryl, phenyl, 2-fluorophenyl, 4-fluorophenyl,2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,1-(2-dimethylamino)naphthyl or 2-thienyl; CH(OH)CH₂NHSO₂CH₃;(CH₂)₃NHSO₂CH(CH₃)₂; COCH₂N(OCOC(CH₃)₂SO₂CH₃; COCH₂NHSO₂CH₃;(CH₂)₂NHCOR¹⁵ in which R¹⁵ represents CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,phenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 2-methoxyphenyl,4-methoxyphenyl, 2-thienyl, CH═CH, CH═CHCN, OCH₃ or O(CH₂)₃CH₃.

Examples of particular values for (L^(a))_(n)—X²—(L^(b))_(m) are a bond,O, NH, S, SO, SO₂, CO, CH₂, COCH₂, COCONH, CH(OH)CH₂, CONH, NHCO,NHCONH, CH₂O, OCH₂, OCH₂CONH, CH₂NH, NHCH₂ and CH₂CH₂, with a bond,CONH, and CH₂O being especially preferred.

R¹⁴ is preferably an unsubstituted or substituted phenyl, naphthyl,furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidylbenzothienyl or benzothiazolyl group.

Examples of particular values for R¹⁴ are phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,4-iodophenyl, 2,3-difluoro-phenyl, 2,4-difluorophenyl,3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,4-cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl,4-methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl,2-prop-2-enylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-bromomethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl,2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetylphenyl,3-acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl,2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-butoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl,3-(1-hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl,2-(1-hydroxypropyl)phenyl, 4-(1-hydroxypropyl)phenyl,2-(1-hydroxy-2,2-dimethyl-propyl)phenyl, 4-trifluoromethoxyphenyl,2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl,4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3-aminopropyl)phenyl,4-carboxyphenyl, 4-carbamoylphenyl, 4-N-methylcarbamoylphenyl,4-N,N-dimethylcarbamoylphenyl, 2-isopropylaminomethylphenyl,4-t-butoxycarbonylaminomethylphenyl,4-(2-isopropoxy-carboxamido)ethylphenyl,4-(2-t-butoxycarboxamido)ethyl-phenyl, 4-isopropylsulfonylaminophenyl,4-(2-methane-sulfonylamino)ethylphenyl,4-(2-ethylsulfonylamino)ethyl-phenyl,4-(3-isopropylsulfonylamino)propylphenyl,4-(1-(2-(2-propane)sulfonylamino)propyl)phenyl,4-(2-propylsulfonylamino)ethylphenyl,4-(2-isopropylsulfonylamino)ethylphenyl,4-(2-butylsulfonylamino)ethylphenyl,4-(1-isopropyl-sulfonylaminomethyl)ethylphenyl,4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonylamino)-ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylamino)-ethylphenyl,4-(2-N,N-dimethylaminosulfonylamino)-ethylphenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl,4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl,4-(N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl,4-(2-(2-thienylcarboxamido)ethyl)phenyl, thien-2-yl,5-hydroxy-methylthien-2-yl, 5-formylthien-2-yl, thien-3-yl,5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2-bromothien-3-yl,fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl,3-bromoisoxazol-5-yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl,5-methylisoxazol-3-yl, 5-hydroxymethylisoxazol-3-yl,5-methyl-3-phenylisoxazol-4-yl, 5-(2-hydroxyethyl)isoxazol-3-yl,5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl,5-N-methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl,3-bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl,4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl,4-carboxythiazol-2-yl, imidazol-1-yl, 2-sulfhydrylimidazol-1-yl,[1,2,4]triazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl,2-ethyltetrazol-5-yl, 2-isopropyl-tetrazol-5-yl,2-(2-propenyl)tetrazol-5-yl, 2-benzyl-tetrazol-5-yl, pyrid-2-yl,5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl,5-trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl,6-methylpyridazin-3-yl, 6-methoxypyrazin-3-yl, pyrimidin-5-yl,benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl.

Examples of an unsubstituted or substituted aromatic or heteroaromaticgroup represented by R¹ are unsubstituted or substituted phenyl, furyl,thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).

Examples of an unsubstituted or substituted (5–8C)cycloalkyl grouprepresented by R¹ are unsubstituted or substituted cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl, with cyclohexyl being preferred.

More preferably, R¹ represents 2-naphthyl or a group of formula

in which

-   -   R²⁰ represents halogen; nitro; cyano; hydroxyimino;        (1–10C)alkyl; (2–10C)alkenyl; (2–10C)alkynyl; (3–8C)cyclo-alkyl;        hydroxy(3–8C)cycloalkyl; oxo(3–8C)cycloalkyl; halo(1–10C)alkyl;        (CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹        represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO,        OCONR¹³, R⁹ represents hydrogen, (1–10C) alkyl, (3–10C)alkenyl,        (3–10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or        (3–8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently        represents hydrogen or (1–10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or        R¹³ together with the nitrogen atom to which they are attached        form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino        group; N-(1–4C)alkylpiperazinyl; N-phenyl(1–4C)alkylpiperazinyl;        thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl;        thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl;        dihydrothienyl; dihydrofuryl; dihydrothiopyranyl;        dihydropyranyl; dihydrothiazolyl;        (1–4C)alkoxycarbonyldihydrothiazolyl;        (1–4C)alkoxycarbonyldimethyl-dihydrothiazolyl;        tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl;        tetrahydropyranyl; indolyl; benzofuryl; benzothienyl;        benzimidazolyl; benzothiazolyl; and a group of formula        R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O,        NH, S, SO, SO₂, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH,        OCH₂CONH or CH═CH, NHCO, L^(a) and L^(b) each represent        (1–4C)alkylene, one of n and m is 0 or 1 and the other is 0, and        R¹⁴ represents a phenyl or hetero-aromatic group which is        unsubstituted or substituted by one or two of halogen; nitro;        cyano; (1–10C)alkyl; (2–10C)alkenyl; (2–10C)alkynyl;        (3–8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);        halo(1–10C)alkyl; cyano(2–10C)alkenyl; phenyl; (CH₂)_(z)X³R¹⁵ in        which z is 0 or an integer of from 1 to 4, X³ represents O, S,        NR¹⁶, CO, CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷,        NHCONH, OCONR¹⁹ or NR¹⁹COO, R¹⁵ represents hydrogen,        (1–10C)alkyl, phenyl(1–4C)alkyl, halo(1–10C)alkyl,        (1–4C)alkoxycarbonyl(1–4C)alkyl,        (1–4C)alkylsulfonylamino(1–4C)alkyl,        (N-(1–4C)alkoxycarbonyl)(1–4C)alkylsulfonylamino(1–4C)alkyl,        (3–10C)alkenyl, (3–10C)alkynyl, (3–8C)cycloalkyl, camphoryl or        an aromatic or heteroaromatic group which is unsubstituted or        substituted by one or two of halogen, (1–4C)alkyl,        halo(1–4C)alkyl, di(1–4C)alkylamino and (1–4C)alkoxy, and R¹⁶,        R¹⁷, R¹⁸ and R¹⁹ each independently represents hydrogen or        (1–10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷, R¹⁸ or R¹⁹ together with the        nitrogen atom to which they are attached form an azetidinyl,        pyrrolidinyl, piperidinyl or morpholino group; and    -   R²¹ represents a hydrogen atom, a halogen atom, a (1–4C)alkyl        group or a (1–4C)alkoxy group.

Examples of particular values for R²⁰ are fluorine, chlorine, bromine,cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, 1,1-dimethylethyl, cyclopentyl, cyclohexyl,3-hydroxycyclopentyl, 3-oxocyclopentyl, methoxy, ethoxy, propoxy,2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido,1-butanoylamido, t-butylcarboxamido, acryloylamido,2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy,morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido,cyclobutylcarboxamido, cyclopentyl-carboxamido, cyclohexylcarboxamido,cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino,piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2-yl,4,5-dihydro-4-methoxy-carbonyl-5,5-dimethylthiazol-2-yl,benzothien-2-yl, benzothiazol-2-yl, phenyl, 2-fluorophenyl,3-fluorophenyl, 2,3-difluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 2-methylphenyl,4-methylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,3-trifluoromethylphenyl, 4-trifluoro-methylphenyl,4-(2-cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyl,4-formylphenyl, 3-acetylphenyl, 4-acetylphenyl, 4-carboxyphenyl,2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl,4-(1-hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl,4-(2-aminoethyl)-phenyl, 4-(3-aminopropyl)phenyl,4-(2-acetylaminoethyl)-phenyl, 4-t-butoxycarboxylaminoethyl)phenyl,4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino,4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonylaminoethyl)phenyl,4-(2-ethylsulfonylaminoethyl)phenyl,4-(2-propylsulfonylaminoethyl)phenyl,4-(2-butylsulfonyl-aminoethyl)phenyl,4-(2-isopropylsulfonylaminoethyl)phenyl,4-(1-hydroxy-2-methanesulfonylaminoethyl)phenyl,4-(2-dimethylaminosulfonylaminoethyl)phenyl,4-(1-(2-(2-propyl)sulfonylaminopropyl)phenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonyl-aminoethyl)phenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4-carbamoylphenyl,4-methyl-carbamoylphenyl, 4-dimethylcarbamoylphenyl,4-(2-(2-methylpropaneamido)ethyl)phenyl,4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido,2-fluorobenzamido, 3-fluorobenzamido, 4-fluorobenzamido,2,4-difluorobenzamido, 3-chlorobenzamido, 4-chlorobenzamido,4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3-methylbenzamido,4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido,4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido,3-trifluoromethylbenzamido, 4-trifluoromethylbenzamido,2-fluoro-4-trifluoromethylbenzamido, 2-methoxybenzamido,3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido,4-phenylphenyl-carboxamido, 4-benzylcarboxamido,4-phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy,2-fluorobenzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonylamino)ethyl)phenyl,4-(2-phenylacetamido)-ethyl)phenyl,4-(methanesulfonylaminoethanoyl)phenyl,4-(N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl,2-thienylcarboxamido, 2-furylcarboxamido,3-(5-methyl-isoxazolyl)carboxamido, 5-isoxazolylcarboxamido,2-benzothienylcarboxamido, 4-(5-methyl-3-phenylisoxazolyl)-carboxamido,4-pyridylcarboxamido, 2-(5-nitrofuryl)carboxamido, 2-pyridylcarboxamido,6-chloro-2-pyridyl-carboxamido, 2-thienylsulfonamido,2-thienylmethylamino, 3-thienylmethylamino, 2-furylmethylamino,3-furylmethylamino, 3-acetylureido and 2-(2-thienyl)ethylureido.

Examples of particular values for R²¹ are hydrogen and chlorine. R²¹ ispreferably ortho to R²⁰.

Examples of particular values for R¹ are 2-naphthyl, 4-bromophenyl,4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl-phenyl,4-isobutylphenyl, 4-t-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl,4-cyclopentylphenyl, 4-cyclohexylphenyl,4-(2-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)-phenyl,4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)phenyl,4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl,4-(piperidin-1-yl)phenyl, 3-chloro-4-piperidin-1-ylphenyl,4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3-fluoro-phenyl)phenyl,4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl,4-(4-formylphenyl)phenyl, 4-(4-methylphenyl)phenyl, and4-(2-methoxyphenyl)phenyl.

The compounds of formula I can be prepared following the variousprocedures set forth below. The reagents and starting materials arereadily available to one of ordinary skill in the art. All substituents,unless otherwise specified are as previously defined.

In Scheme I, step A the compound of structure (1) is combined with thecompound of structure (2) under conditions well known in the art toprovide the compound of structure (3). More specifically, for example,the compound (1) is dissolved in a suitable organic solvent. Examples ofsuitable organic solvents include methylene chloride, tetrahydrofuran,and the like. The solution is treated with a slight excess of a suitablebase, and then cooled to about −78° C. to about 0° C. Examples ofsuitable bases include triethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like. To the stirringsolution is added one equivalent of compound (2). The term “Lg” as usedherein refers to a suitable leaving group. Examples of suitable leavinggroups include, Cl, Br, methanesulfonyloxy, trifluoromethanesulfonyloxy,benzenesulfonyloxy, p-toluenesulfonyloxy, and the like. Cl is thepreferred leaving group. The reaction mixture is stirred at about 0° C.to about 50° C. for about 0.5 hours to about 16 hours. The compound (3)is then isolated and purified by techniques well known in the art, suchas extraction techniques and chromatography. For example, the mixture iswashed with 10% sodium bisulfate, the layers separated and the aqueousextracted with several times with a suitable organic solvent, such asmethylene chloride. The organic extracts are combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue is then purified by flash chromatography on silica gel with asuitable eluent such as ethyl acetate/hexane to provide the compound(3).

In Scheme I, step B the compound of structure (3) is fluorinated underconditions well known in the art to provide the compound of formula Ia.For example, compound (3) is dissolved in a suitable organic solvent,such as methylene chloride and the solution is cooled to about −78° C.under an inert atmosphere, such as nitrogen. To this solution is addedslowly, about one equivalent of diethylaminosulfur trifluoride (DAST)dissolved in a suitable organic solvent, such as methylene chloride withstirring. The reaction is then allowed to warm to room temperature(about 22° C.) and the compound of formula Ia is then isolated andpurified using techniques and procedures well known in the art, such asextraction techniques and chromatography. For example, the reaction isdiluted with water and methylene chloride. The layers are separated andthe organic layer is washed with water, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to provide the crudecompound of formula Ia. This crude material can then be purified bystandard techniques, such as recrystallization from a suitable eluent,or flash chromatography or radial chromatography (radial chromatographyis carried out using a Chromatotron, Harrison Research Inc., 840 MoanaCourt, Palo Alto, Calif. 94306) on silica gel, with a suitable eluent,such as hexane/ethyl acetate to provide purified compound of formula Ia.

Alternatively, in Scheme I, step B′ the compound (1) is fluorinated in amanner analogous to the procedure described in step B above with DAST toprovide the compound of structure (4). In Scheme I, step A′ compound (4)converted to the compound of formula Ia in a manner analogous to theprocedure described in step A above.

In Scheme II, step A compound (1) is converted to the carbamate (6)under standard carbamate forming conditions well known to one ofordinary skill in the art. For examples of standard carbamate formingconditions see J. March, “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure,” 2^(nd) Edition, McGraw Hill Inc., (1977)pages 382–383, and T. W Green, “Protective Groups in Organic Synthesis,”John Wiley & Sons, Inc. (1981) pages 223–248.

More specifically, for example, compound (1) is dissolved in a suitableorganic solvent, such as tetrahydrofuran or methylene chloride andtreated with an equivalent of a compound (5) wherein “Lg” represents asuitable leaving group. Examples of suitable leaving groups are Cl, Br,I, and the like. The reaction can be performed at a temperature of fromabout −10° C. to about 50° C., preferably at a temperature of about 0°C. to about 25° C. After about 2 hours to about 12 hours, the carbamate(6) is isolated and purified by techniques well known in the art, suchas extraction techniques and chromatography. For example, the reactionis diluted with a suitable organic solvent, such as methylene chloride,rinsed with saturated sodium bicarbonate, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum. The crudeproduct can then be purified by flash chromatography on silica gel witha suitable eluent, such ethyl acetate/hexanes to provide the purifiedcarbamate (6).

In Scheme II, step B carbamate (6) is converted to the compound offormula Ib in a manner analogous to the procedure set forth in Scheme I,step B.

Alternatively, in Scheme II, step B′ the compound (1) is fluorinated ina manner analogous to the procedure described in step B above with DASTto provide the compound of structure (7). In Scheme II, step A′ compound(7) is converted to the compound of formula Ib in a manner analogous tothe procedure described in step A above.

In Scheme III, step A urea (9) is prepared from compound (1) understandard urea forming conditions well known to one of ordinary skill inthe art. For examples of standard urea forming conditions see J. March,“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,”2^(nd) Edition, McGraw Hill Inc., (1977) page 823, and T. W Green,“Protective Groups in Organic Synthesis,” John Wiley & Sons, Inc. (1981)pages 248–49.

More specifically, for example, a compound (1) is dissolved in asuitable organic solvent, such as methylene chloride, and the solutionis treated with about 1.1 equivalents of an isocyanate (8). The reactioncan be performed at a temperature of about −10° C. to about 50° C. forabout 2 hours to about 12 hours to provide the urea (9). The urea (9)can be isolated and purified by techniques well known in the art, suchas extraction techniques and chromatography. For example, the reactionis diluted with a suitable organic solvent, such as methylene chloride,rinsed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The crude product can then be purified byflash chromatography on silica gel with a suitable eluent, such ethylacetate/hexanes to provide the purified urea (9).

In Scheme III, step B urea (9) is converted to the compound of formulaIc in a manner analogous to the procedure set forth in Scheme I, step B.

Alternatively, in Scheme III, step B′ the compound (1) is fluorinated ina manner analogous to the procedure described in step B above with DASTto provide the compound of structure (10). In Scheme III, step A′compound (10) is converted to the compound of formula Ic in a manneranalogous to the procedure described in step A above.

The compounds of formula I in which R¹ represents a 4-bromophenyl group,a 4-iodophenyl group or a 4-(triflate)phenyl group may conveniently beconverted into other compounds of formula I in which R representsanother 4-substituted phenyl group under conditions well known in theart, such as by reaction with an appropriate boronic acid derivative,for example, a benzeneboronic acid derivative. See for example,International Publication Number WO 98/33496, published Aug. 6, 1998,the disclosure of which is hereby incorporated by reference. Morespecifically, the reaction is conveniently performed in the presence ofa tetrakis (triarylphosphine)palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base such as potassium carbonate.Convenient solvents for the reaction include aromatic hydrocarbons, suchas toluene. The temperature at which the reaction is conducted isconveniently in the range of from 0 to 150° C., preferably 75 to 120° C.Bis aromatic intermediates useful in the preparation of compounds offormula I may be prepared by reacting a bromoaromatic orbromoheteroaromatic compound with an aromatic or heteroaromatic boronicacid in an analogous manner.

Alternatively, the coupling reaction may be carried out using palladiumdiacetate with a suitable organic solvent, such as n-propanol oracetone. See for example, Organic Synthesis 1998, 75, 61; Goodson, F.E.; Wallow, T. I.; Novak, B. M. and Organic Synthesis 1998, 75, 53;Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. whereinanalogous coupling conditions are employed.

The boronic acid derivative used as a starting material may be preparedby reacting a trialkyl borate, such as triisopropyl borate with anappropriate organolithium compound at reduced temperature. For example,2-fluorobenzeneboronic acid may be prepared by reacting2-fluorobromobenzene with butyllithium in tetrahydrofuran at about −78°C. to afford 2-fluorophenyl lithium, and then reacting thisorganolithium compound with triisopropyl borate. This is followed byhydrolysis with aqueous HCl.

Alternatively, the compounds of formula I in which R¹ represents a4-bromophenyl group may be converted to a 4-(trimethylstannyl)phenyl or4-(tri-n-butylstannyl)phenyl group by treatment of the correspondingbromide with a palladium(0) catalyst, such astetrakis(triphenylphosphine)-palladium(0) and hexaalkyldistannane, wherethe alkyl group is methyl or n-butyl, in an aprotic solvent such astoluene in the presence of a tertiary amine base such as triethylamine,at temperatures ranging from 80 to 140° C., preferably from 90 to 110°C.

The compounds of formula I in which R¹ represents a4-(tri-n-butylstannyl)phenyl group may then be reacted with an aryl- orheteroarylbromide, such as 2-bromothiophene-5-carboxaldehyde, or anaryl- or heteroaryliodide, or an aryl- or heteroaryltriflate, in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), or a palladium(II) catalyst,such as bis(triphenylphosphine)-palladium(II) dichloride, in an aproticsolvent, such as dioxane, at temperatures ranging from 80 to 140° C.,preferably from 90 to 110° C., to afford the corresponding4-(aryl)phenyl or 4-(heteroaryl)phenyl substituted compound.

The compounds of formula I in which R¹ represents a 4-bromophenyl groupmay be converted into other compounds of formula I in which R¹represents a 4-substituted alkyl- or cycloalkylphenyl group, such as4-cyclopentylphenyl by treatment of the corresponding bromide with anappropriate alkyl- or cycloalkyl Grignard reagent, such ascyclopentyl-magnesium bromide, in the presence of a palladium(II)catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)(PdCl₂(dppf)),in an aprotic solvent, such as diethyl ether at temperatures rangingfrom −78° C. to 25° C.

The compounds of formula I in which R¹ represents a 4-bromophenyl groupmay be converted into a 4-substitutedcarboxyaldehydephenyl(formylphenyl) group by reaction of thecorresponding bromide with the carbon monoxide gas which is bubbled intothe reaction under atmospheric pressure in the presence of apalladium(II) catalyst, such as bis(triphenyl-phosphine)palladium(II)dichloride and sodium formate in an aprotic solvent, such asdimethylformamide at temperatures ranging from 70 to 110° C., preferablyat 90° C.

The compounds of formula I in which R¹ represents a 4-hydroxyphenylgroup may be converted into other compounds of formula I in which R¹represents an alkoxy group by treatment of the correspondinghydroxyphenyl group with an appropriate alkylhalide such asbenzylbromide in the presence of sodium hydride in an aprotic solventsuch as dimethylformamide at temperatures ranging from 25 to 100° C.,preferably from 50 to 90° C.

The compounds of structure (1a) can be prepared following the proceduredescribed in Scheme IV. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. All substituents, unlessotherwise specified are as previously defined.

In Scheme IV, step A the compound of structure (11) is converted to thecompound of structure (12) under standard conditions. For example, seeGreenlee and Hangauer, Tetrahedron Lett., 24(42), 4559 (1983). Forexample, compound (11) is dissolved in a suitable organic solvent, suchas dry tetrahydrofuran, containing excess 18-crown-6, and excesspotassium cyanide. To this mixture at room temperature is added dropwiseabout 1.2 equivalents of cyanotrimethylsilane. The reaction mixture isallowed to stir for about 1 to 4 hours to provide compound (12).Compound (12) is then carried on directly to step B without isolation.

Alternatively, in Scheme IV, step A, for example, compound (11) iscombined with a catalytic amount of zinc iodide followed by slowaddition of excess trimethylsilyl cyanide with the generation of heat.The resulting solution is stirred at room temperature under nitrogen forabout 8 to 16 hours. The mixture is then diluted with a suitable organicsolvent, such as chloroform, washed with saturated sodium bicarbonate,water, brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum to provide compound (12).

In Scheme IV, step B compound (12) is converted to compound of structure(1a). For example, compound (11) prepared above, still in solution, istreated with a solution of about 1.4 equivalents of borane indimethylsulfide. The reaction mixture is then heated to reflux for about16 hours and then cooled to room temperature. The reaction mixture isthen cautiously treated with anhydrous HCl in methanol and allowed tostir for about one hour. The product (1a) is then isolated and purifiedusing standard techniques and procedures. For example, the solvent isremoved under vacuum and the residue triturated with a suitable organicsolvent, such at methy t-butyl ether and the solid is collected byfiltration. The solid is then suspended in methylenechloride/tetrahydrofuran mixture (1:2.4) and treated with 1N NaOH untilabout pH 12.3 is reached. The phases are separated and the organic phaseis rinsed with brine. The organic phase is then concentrated undervacuum and the residue triturated with diethyl ether to provide thepurified compound (1a). Compound (1a) is then used in Schemes I, II andIII in a manner analogous to the procedures described for compound (1).

More specifically, compounds of structure (1a′) can be prepared asdisclosed in Scheme V. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. All substituents, unlessotherwise specified are as previously defined.

In Scheme V, step A, the compound of structure (11a) is converted to thecompound of structure (12a) in a manner analogous to the proceduredescribed in Scheme IV, step A.

In Scheme V, step B, the compound of structure (12a) is converted to thecompound of structure (1a′) in a manner analogous to the proceduredescribed in Scheme IV, step B. Compound (1a′) can then be converted toa sulfonamide, carbamate or urea in a manner analogous to the proceduresdescribed in Schemes I, II and III above. The resulting sulfonamide,carbamate, or urea can then be fluorinated with DAST in a manneranalogous to the procedures set forth above in Schemes I, II and III.The resulting fluorinated product possessing a nitro substituent on thephenyl group can then be hydrogenated under standard conditions wellknown to one of ordinary skill in the art to provide the correspondingamino substituted compound. For example, see J. March, “Advanced OrganicChemistry: Reactions, Mechanisms, and Structure,” second edition, 1977,1968 McGraw-Hill, Inc., pages 1125–1126.

In addition, compounds of structure (1a″) can be prepared as disclosedin Scheme Va. The reagents and starting materials are readily availableto one of ordinary skill in the art. All substituents, unless otherwisespecified are as previously defined.

In Scheme Va, step A, the compound of structure (11a′) is converted tothe compound of structure (12a′) in a manner analogous to the proceduredescribed in Scheme IV, step A.

In Scheme Va, step B, the compound of structure (12a′) is converted tothe compound of structure (1a″) in a manner analogous to the proceduredescribed in Scheme IV, step B. Compound (1a″) can then be converted toa sulfonamide, carbamate or urea in a manner analogous to the proceduresdescribed in Schemes I, II and III above. The resulting sulfonamide,carbamate, or urea can then be fluorinated with DAST in a manneranalogous to the procedures set forth above in Schemes I, II and III.

The compounds of formula Id and formula Ie can be prepared following theprocedure described in Scheme VI. The reagents and starting materialsare readily available to one of ordinary skill in the art. Allsubstituents, unless otherwise specified are as previously defined.

In Scheme VI, step A the compound of structure (13) is coupled withcompound of structure (14) under standard conditions to provide compoundof structure (15). For example, compound (13) is combined with about 1.5equivalents of compound (14), about 1.5 equivalents of potassiumcarbonate, and about 0.06 equivalents of tetrakis(triphenylphosphine)palladium(0) in a suitable solvent or solvent mixture, such asdioxane/water (3:1). The mixture is then heated at about 100° C. forabout 18 hours. The reaction is then cooled and compound (15) isisolated and purified using standard techniques and procedures, such asextraction techniques and chromatography. For example, the reactionmixture is extracted with a suitable organic solvent, such as ethylacetate, the organic extracts are combined, washed with water, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The crude material is then purified by chromatography on silica gel witha suitable eluent, such as hexane/ethyl acetate to provide purifiedcompound (15).

In Scheme VI, step B, compound (15) is fluorinated under standardconditions to provide the compound of formula Ie. For example, compound(15) is dissolved in a suitable organic solvent, such as methylenechloride is added to about one equivalent of DAST at about −78° C. withstirring under an atmosphere of nitrogen. The reaction is allowed towarm to room temperature and the compound of formula Ie is isolated andpurified using standard techniques, such as extraction techniques andchromatography. For example, the reaction mixture is diluted with waterand a suitable organic solvent, such as methylene chloride. The layersare separated and the organic layer is washed with water, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Thecrude material is then purified by chromatography on silica gel with asuitable eluent, such as hexane/ethyl acetate to provide the purifiedcompound of formula Ie.

Alternatively, in Scheme VI, step B′ the compound (13) is fluorinated toprovide the compound of formula Id in a manner analogous to theprocedure described above in step B.

In addition, in Scheme VI, step A′ the compound of formula Id isconverted to the compound of formula Ie in a manner analogous to theprocedure described above in step A.

More specifically, compounds of formula Ig and formula Ih can beprepared as shown in Scheme VII. Reagents and starting materials arereadily available to one of ordinary skill in the art, for example, seeInternational Patent Application No. PCT/US99/03449, published Sep. 2,1999. All substituents, unless otherwise specified, are previouslydefined.

In Scheme VII, step A the compound of formula If wherein Q represents a(3–8C)cycloalkyl, an aromatic group, unsubstituted or substituted, suchas phenyl, or a heteroaromatic group, unsubstituted or substituted,R^(c) represents hydrogen, hydroxy, (1–4C)alkoxy, (1–4C)alkoxycarbonyl,or together with R^(p) a bond, R^(p) represents hydrogen, hydroxy, ortogether with R^(c) a bond, q is an integer 1, 2, 3 or 4, R³⁰ represents(1–6C)alkyl, (3–6C)cycloalkyl, fluoro(1–6C)alkyl, chloro(1–6C)alkyl,(2–6C)alkenyl, (1–4C)alkoxy(1–4C)alkyl, phenyl which is unsubstituted orsubstituted by halogen, (1–4C)alkyl or (1–4C)alkoxy, (1–4C)alkylphenylwherein the phenyl group is unsubstituted or substituted by halogen,(1–4C)alkyl or (1–4C)alkoxy, and the remaining substituents are definedas hereinabove, is converted to the amine of formula Ig under conditionswell known in the art. For example, compound If is dissolved in asuitable organic solvent, such as tetrahydrofuran and heat to reflux. Tothe refluxing solution is added about 1.1 equivalents of a boranereagent, such as borane dimethylsulfide complex. The reaction mixture isthen heated at reflux for about 1 to 2 hours, cooled to room temperatureand then treated with 6N HCl. The reaction is again heated at reflux forabout 1 hour, cooled and the pH is adjusted to about pH 10 with aqueoussodium hydroxide. The product, compound Ig, is then isolated andpurified by standard techniques such as extraction and chromatography.

For example, the reaction mixture is diluted with water and extractedwith a suitable organic solvent, such as dichloromethane. The organicextracts are combined, dried over anhydrous magnesium sulfate, filteredand concentrated under vacuum to provide formula Ig.

In Scheme VII, step B the compound of formula Ig is sulfonylated toprovide the compound of formula Ih under conditions well known in theart. For example, compound Ig is dissolved in a suitable organicsolvent, such as dichloromethane, followed by addition of about 1.05equivalents of triethylamine. The solution is cooled to about 0° C. andtreated with about 1.05 equivalents of a suitable sulfonyl chloride offormula R³⁰SO₂Cl, such as methanesulfonyl chloride. The reaction is thenallowed to warm to room temperature over 2 hours with stirring. Theproduct compound Ih, is then isolated and purified using techniques wellknown to one of ordinary skill in the art, such as extraction andchromatography.

For example, the reaction mixture is then diluted with a suitableorganic solvent, such as dichloromethane and 10% aqueous sodiumbisulfate. The organic layer is separated and the aqueous layer isextracted with dichloromethane. The organic layer and extracts are thencombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to provide compound Ih. Compound Ih can then be purified byflash chromatography on silica gel with a suitable eluent, such as ethylacetate/hexane to provide purified compound Ih.

More specifically, compounds of formula Ij and formula Ik can beprepared as shown in Scheme VIII. Reagents and starting materials arereadily available to one of ordinary skill in the art. All substituents,unless otherwise specified, are previously defined.

In Scheme VIII, step A the compound of formula If can be hydrolyzedunder standard conditions to provide the compound of formula Ij. Forexample, compound If is dissolved in a suitable organic solvent, such asdioxane and treated with a suitable base, such as sodium hydroxide. Thereaction mixture is then heated at about 100° C. for about 24 hours. Thereaction mixture is then cooled to room temperature and acidified with10% sodium bisulfate. Compound Ij is then isolated and purified bytechniques well known in the art, such as extraction and chromatography.

For example, the reaction mixture is extracted with a suitable organicsolvent, such as ethyl acetate, the organic extracts are combined, driedover anhydrous magnesium sulfate, filtered and concentrated under vacuumto provide compound Ij. Compound Ij can be purified by flashchromatography on silica gel with a suitable eluent, such asmethanol/chloroform.

In Scheme VIII, step B the compound of formula Ij can be esterifiedunder conditions well known in the art to provide the compound offormula Ik. For example, compound Ij is dissolved in a suitable organicsolvent of formula R⁴⁰OH, wherein R⁴⁰ represents (1–6C)alkyl,(3–6C)cycloalkyl, fluoro(1–6C)alkyl, chloro(1–6C)alkyl, (2–6C)alkenyl,(1–4C)alkoxy(1–4C)alkyl, phenyl which is unsubstituted or substituted byhalogen, (1–4C)alkyl or (1–4C)alkoxy, (1–4C)alkylphenyl wherein thephenyl group is unsubstituted or substituted by halogen, (1–4C)alkyl or(1–4C)alkoxy, such as ethanol and HCl gas is bubbled through thesolution until the mixture is saturated. The reaction mixture is thenheated at 60° C. for about 24 hours, then cooled to room temperature andconcentrated under vacuum. Additional ethanol is added to the residueand the mixture is again concentrated under vacuum to provide the ethylester of compound Ik. Compound Ik can be then be purified by flashchromatography on silica gel with a suitable eluent, such ethylacetate/hexane.

More specifically, compounds of formula Im can be prepared as shown inScheme IX. Reagents and starting materials are readily available to oneof ordinary skill in the art. All substituents, unless otherwisespecified, are previously defined.

In Scheme IX, step A compound Ij is readily converted to the amide offormula Im under conditions well known in the art. For example, compoundIj is dissolved in a suitable organic solvent, such as tetrahydrofuranand treated with an excess of thionyl chloride. The reaction mixture isstirred at room temperature for about 16 hours and then concentratedunder vacuum. The residue is then dissolved in a suitable organicsolvent, such as methylene chloride. The solution is added to a solutionof one equivalent of a suitable amine of formula R³¹R³²NH, wherein R³¹and R³² independently represent (1–4C)alkyl or together with thenitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl oroctahydroazocinyl group, such as dimethylamine in dichloromethane withstirring. The mixture is stirred for about 2 hours at about 0° C. andthen 10% aqueous sodium bisulfate is added. Compound Im is then isolatedand purified by techniques well known in the art, such as extraction andflash chromatography.

For example, the reaction mixture is then extracted with a suitableorganic solvent, such as methylene chloride, the organic extracts arecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to provide compound Im. This can then be purified by flashchromatography on silica gel with a suitable eluent, such as ethylacetate/hexane to provide the purified compound Im.

Compounds of formula In can be prepared as shown in Scheme X. Reagentsand starting materials are readily available to one of ordinary skill inthe art. All substituents, unless otherwise specified, are previouslydefined.

In Scheme X, step A, the compound of structure (1) is combined with acompound of formula ClSO₂NR³R⁴ under standard conditions to provide thecompound of structure (16). For example, compound (1) is dissolved in asuitable organic solvent, such as tetrahydrofuran and treated with aboutone equivalent of a suitable base, such as DBU at about 0° C. Thesolution is then treated with about one equivalent of a compound offormula ClSO₂NR³R⁴. The reaction is then allowed to warm to roomtemperature and stirred for about 4 to 16 hours. The reaction is thenconcentrated under vacuum to provide the crude product (16) which canthen be purified by chromatography on silica gel with a suitable eluent,such as ethyl acetate/hexane.

In Scheme X, step B, compound (16) is converted to the compound offormula In in a manner analogous to the procedure set forth in Scheme I,step B.

Alternatively, in Scheme X, step B′ the compound (1) is fluorinated in amanner analogous to the procedure described in Scheme I, step B withDAST to provide the compound of structure (17). In Scheme X, step A′compound (17) is converted to the compound of formula In in a manneranalogous to the procedure described above in step A.

Compounds of formula Ip can be prepared as shown in Scheme XI. Reagentsand starting materials are readily available to one of ordinary skill inthe art. All substituents, unless otherwise specified, are previouslydefined.

In Scheme XI, step A, the phenol of structure (18) is alkylated with asuitable alkylating agent of structure R^(alk)-Hal under standardconditions wherein Hal is Br or Cl, and R^(alk) is an unsubstituted orsubstituted aromatic group, an unsubstituted or substitutedheteroaromatic group, an unsubstituted or substituted (5–8C)cycloalkylgroup, (1–10C) alkyl; (2–10C)alkenyl; or (2–10C)alkynyl to provide thecompound of structure (19). For example, compound (18) is added to aboutone equivalent of a suitable base, such as sodium hydride, in a suitableorganic solvent, such as dimethylformamide. The reaction mixture isstirred for about 30 minutes at room temperature and treated with aboutone equivalent of a suitable alkylating agent R^(alk)-Hal followed byaddition of sodium iodide. The reaction is heated at about 100° C. forabout 2 hours and then cooled. The reaction is diluted with water,extracted with a suitable organic solvent, such as ethyl acetate, theorganic extracts are combined, washed with water, dried over anhydroussodium sulfate, filtered, and concentrated to provide crude compound(19). The crude material can be purified by chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane.

In Scheme X, step B, the compound (19) is fluorinated in a manneranalogous to the procedure described in Scheme I, step B with DAST toprovide the compound of formula Ip.

Compounds of formula Iq can be prepared as shown in Scheme XII. Reagentsand starting materials are readily available to one of ordinary skill inthe art. All substituents, unless otherwise specified, are previouslydefined.

In Scheme XII, step A, the compound of structure (20) is converted tothe amide of structure (21) under standard amide coupling conditionswell known in the art. For example, the compound (20) is dissolved in asuitable organic solvent, such as methylene chloride, and treated with acatalytic amount of dimethylaminopyridine (DMAP), about 1.6 equivalentsof 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, and about oneequivalent of a suitable acid of formula R^(alk)CO₂H. R^(alk) is anunsubstituted or substituted aromatic group, an unsubstituted orsubstituted heteroaromatic group, an unsubstituted or substituted(5–8C)cycloalkyl group, (1–10C) alkyl; (2–10C)alkenyl; or(2–10C)alkynyl. The reaction mixture is stirred at room temperature forabout 4 to 64 hours and poured into water. The quenched reaction mixtureis then extracted with a suitable organic solvent, such as ethylacetate, the combined organic extracts are washed with water, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum toprovide crude (21). The crude material can be purified by chromatographyon silica gel with a suitable eluent, such as ethyl acetate/hexane.

Alternatively, in Step A, compound 20 is dissolved in a suitable organicsolvent, such as tetrahydrofuran with about 1.2 equivalents oftriethylamine added. The solution is then treated dropwise with aboutone equivalent of an acid chloride of formula R^(alk)COCl. R^(alk) is anunsubstituted or substituted aromatic group, an unsubstituted orsubstituted heteroaromatic group, an unsubstituted or substituted(5–8C)cycloalkyl group, (1–10C) alkyl; (2–10C)alkenyl; or(2–10C)alkynyl. The reaction mixture is stirred at room temperature forabout 2 to 24 hours and poured into water. The quenched reaction mixtureis then extracted with a suitable organic solvent, such as ethylacetate, the combined organic extracts are washed with water, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum toprovide crude (21). The crude material can be purified by chromatographyon silica gel with a suitable eluent, such as ethyl acetate/hexane.

In Scheme XII, step B, the compound (21) is fluorinated in a manneranalogous to the procedure described in Scheme I, step B with DAST toprovide the compound of formula Iq.

The ability of compounds of formula I to potentiate glutamatereceptor-mediated response may be determined using fluorescent calciumindicator dyes (Molecular Probes, Eugene, Oreg., Fluo-3) and bymeasuring glutamate-evoked efflux of calcium into GluR4 transfectedHEK293 cells, as described in more detail below.

In one test, 96 well plates containing confluent monolayers of HEK 293cells stably expressing human GluR4B (obtained as described in EuropeanPatent Application Publication Number EP-A1-583917) are prepared. Thetissue culture medium in the wells is then discarded, and the wells areeach washed once with 200 μl of buffer (glucose, 10 mM, sodium chloride,138 mM, magnesium chloride, 1 mM, potassium chloride, 5 mM, calciumchloride, 5 mM, N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid],10 mM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutesin the dark with 20 μM Fluo3-AM dye (obtained from Molecular ProbesInc., Eugene, Oreg.) in buffer in each well. After the incubation, eachwell is washed once with 100 μl buffer, 200 μl of buffer is added andthe plates are incubated for 30 minutes.

Solutions for use in the test are also prepared as follows. 30 μM, 10μM, 3 μM and 1 μM dilutions of test compound are prepared using bufferfrom a 10 mM solution of test compound in DMSO. 100 μM cyclothiazidesolution is prepared by adding 3 μl of 100 mM cyclothiazide to 3 ml ofbuffer. Control buffer solution is prepared by adding 1.5 μl DMSO to498.5 μl of buffer.

Each test is then performed as follows. 200 μl of control buffer in eachwell is discarded and replaced with 45 μl of control buffer solution. Abaseline fluorescent measurement is taken using a FLUOROSKAN IIfluorimeter (Obtained from Labsystems, Needham Heights, Mass., USA, aDivision of Life Sciences International Plc). The buffer is then removedand replaced with 45 μl of buffer and 45 μl of test compound in bufferin appropriate wells. A second fluorescent reading is taken after 5minutes incubation. 15 μl of 400 μM glutamate solution is then added toeach well (final glutamate concentration 100 μM), and a third reading istaken. The activities of test compounds and cyclothiazide solutions aredetermined by subtracting the second from the third reading(fluorescence due to addition of glutamate in the presence or absence oftest compound or cyclothiazide) and are expressed relative to enhancefluorescence produced by 100 μM cyclothiazide.

In another test, HEK293 cells stably expressing human GluR4 (obtained asdescribed in European Patent Application Publication No. EP-A1-0583917)are used in the electrophysiological characterization of AMPA receptorpotentiators. The extracellular recording solution contains (in mM): 140NaCl, 5 KCl, 10 HEPES, 1 MgCl₂, 2 CaCl₂, 10 glucose, pH=7.4 with NaOH,295 mOsm kg-1. The intracellular recording solution contains (in mM):140 CsCl, 1 MgCl₂, 10 HEPES,(N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA(ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH=7.2 with CsOH,295 mOsm kg-1. With these solutions, recording pipettes have aresistance of 2–3 MΩ. Using the whole-cell voltage clamp technique(Hamill et al. (1981) Pflügers Arch., 391: 85–100), cells arevoltage-clamped at −60 mV and control current responses to 1 mMglutamate are evoked. Responses to 1 mM glutamate are then determined inthe presence of test compound. Compounds are deemed active in this testif, at a test concentration of 10 μM or less, they produce a greaterthan 10% increase in the value of the current evoked by 1 mM glutamate.

In order to determine the potency of test compounds, the concentrationof the test compound, both in the bathing solution and co-applied withglutamate, is increased in half log units until the maximum effect wasseen. Data collected in this manner are fit to the Hill equation,yielding an EC₅₀ value, indicative of the potency of the test compound.Reversibility of test compound activity is determined by assessingcontrol glutamate 1 mM responses. Once the control responses to theglutamate challenge are re-established, the potentiation of theseresponses by 100 μM cyclothiazide is determined by its inclusion in boththe bathing solution and the glutamate-containing solution. In thismanner, the efficacy of the test compound relative to that ofcyclothiazide can be determined.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of formula I or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable diluent or carrier.

The pharmaceutical compositions are prepared by known procedures usingwell-known and readily available ingredients. In making the compositionsof the present invention, the active ingredient will usually be mixedwith a carrier, or diluted by a carrier, or enclosed within a carrier,and may be in the form of a capsule, sachet, paper, or other container.When the carrier serves as a diluent, it may be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. The compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols, ointments containing, forexample, up to 10% by weight of active compound, soft and hard gelatincapsules, suppositories, sterile injectable solutions, and sterilepackaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia,calcium phosphate, alginates, tragcanth, gelatin, calcium silicate,micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 mg to about 500 mg, more preferably about5 mg to about 300 mg (for example 25 mg) of the active ingredient. Theterm “unit dosage form” refers to a physically discrete unit suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient. The following formulationexamples are illustrative only and are not intended to limit the scopeof the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 MagnesiumStearate  10 Total 460

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Tablets each containing 60 mg of active ingredient are made as follows:

Quantity (mg/tablet) Active Ingredient 60 Starch 45 MicrocrystallineCellulose 35 Polyvinylpyrrolidone 4 Sodium Carboxymethyl Starch 4.5Magnesium Stearate 0.5 Talc 1 Total 150

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

As used herein the term “patient” refers to a mammal, such as a mouse,guinea pig, rat, dog or human. It is understood that the preferredpatient is a human.

As used herein, the terms “treating” or “to treat” each mean toalleviate symptoms, eliminate the causation either on a temporary orpermanent basis, or to prevent or slow the appearance of symptoms of thenamed disorder. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

As used herein, the term “effective amount” refers to the amount of acompound of formula I which is effective, upon single or multiple doseadministration to a patient, in treating the patient suffering from thenamed disorder.

An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of mammal; its size, age, and general health; thespecific disease or disorder involved; the degree of or involvement orthe severity of the disease or disorder; the response of the individualpatient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The compounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal orintranasal routes. Alternatively, the compound may be administered bycontinuous infusion. A typical daily dose will contain from about 0.01mg/kg to about 100 mg/kg of the active compound of this invention.Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, morepreferably from about 0.1 mg/kg to about 25 mg/kg.

The following examples and preparations represent typical syntheses ofthe compounds of formula I as described generally above. These examplesare illustrative only and are not intended to limit the invention in anyway. The reagents and starting materials are readily available to one ofordinary skill in the art. As used herein, the following terms have themeanings indicated: “eq” refers to equivalents; “g” refers to grams;“mg” refers to milligrams; “L” refers to liters: “mL” refers tomilliliters; “μL” refers to microliters; “mol” refers to moles; “mmol”refers to millimoles; “psi” refers to pounds per square inch; “min”refers to minutes; “h” or “hr” refers to hours; “° C.” refers to degreesCelsius; “TLC” refers to thin layer chromatography; “HPLC” refers tohigh performance liquid chromatography; “R_(f)” refers to retentionfactor; “R_(t)” refers to retention time; “δ” refers to part per milliondown-field from tetramethylsilane; “THF” refers to tetrahydrofuran;“DMF” refers to N,N-dimethylformamide; “DMSO” refers to methylsulfoxide; “LDA” refers to lithium diisopropylamide; “EtOAc” refers toethyl acetate; “aq” refers to aqueous; “iPrOAc” refers to isopropylacetate; “methyl DAST” refers to dimethylaminosulfur trifluoride, “DAST”refers to diethylaminosulfur trifluoride, “DBU” refers to1,8-diazabicyclo[5.4.0]undec-7-ene; and “RT” refers to room temperature.

EXAMPLE 1 Preparation of[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine

Preparation of 1-Amino-2-(4-iodophenyl)propan-2-ol

Scheme IV, Step A: The trimethylsilyl-protected cyanohydrin derivativeof 4-iodoacetophenone was prepared in situ following generally themethod disclosed by Greenlee and Hangauer, Tetrahedron Lett., 24(42),4559 (1983). Accordingly, cyanotrimethylsilane (21.4 g, 0.216 mol) wasadded dropwise over 5 minutes to a dry, room temperature solutioncontaining 4-iodoacetophenone (44.3 g, 0.180 mol), 18-crown-6 (1.6 g,6.1 mmoles) and KCN (1.17 g, 0.018 mol) in THF (100 mL). The resultingsolution was allowed to stir for 2.5 h. TLC analysis (3:7 EtOAc/Hexanes)showed consumption of starting acetophenone.

Scheme IV, step B: A 10M solution of borane in dimethylsulfide (25 mL,0.25 mol) was added rapidly to the reaction solution and the resultingmixture was heated at reflux for 16 h. The mixture was cooled to roomtemperature and anhydrous 10% (by wt) HCl in methanol was added slowlyover 1 h (GAS EVOLUTION). The solution was allowed to stir for anadditional hour, and was concentrated under reduced pressure to give thecrude title compound as white solid and as the hydrochloride salt. Thissalt was triturated with methyl t-butyl ether and filtered. The freebase was prepared by adding 1N NaOH to a suspension of the HCl salt inCH₂Cl₂ (150 mL) and THF (350 mL) until pH 12.3 was reached. The phaseswere separated and the organic phase was washed with brine (25 mL). Theorganic phase containing the free amine was concentrated under reducedpressure and the resulting solids were triturated with diethyl ether (30mL) to afford the intermediate title compound (35.6 g, 71.3%) as anoff-white powder after vacuum drying. ¹H NMR (CD₃OD, 300 MHz): δ 7.68(d, 2H, J=8.4), 7.24 (d, 2H, J=8.7), 2.78 (m, 2H), 1.46 (s, 3H).

Preparation of[2-Hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine

Scheme I, Step A: Into a 250 mL 3 necked flask fitted with a stirrer andthermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g,0.011 mol) to 1-amino-2-(4-iodophenyl)propan-2-ol (2.77 gm, 0.01 mol) in125 mL CH₂Cl₂ while stirring at 0° C. under nitrogen. The reaction wasthen allowed to warm to room temperature and stirred overnight at thistemperature. In the morning, the mixture was poured into H₂O and thelayers were separated. The organic layer was washed once with H₂O, driedover anhydrous Na₂SO₄, filtered, and concentrated under reduced vacuum.The resulting semi-solid was purified via silica gel chromatographyemploying the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc3:1 to provide the intermediate title compound (744 mg, 19%) as a solidmaterial. FDMS 382 (M*).

Analysis for C₁₂H₁₈NO₃S I:

Theory: C, 37.61 H, 4.73 N, 3.65 Found: C, 38.08 H, 4.26 N, 3.55

Alternative Preparation of Title Compound

Scheme I, step A: In a 250 mL-3 neck flask fitted with a stirrer andthermometer, 2.10 g. of propanesulfonyl chloride was added dropwise to2.77 g. of 1-amino-2-(4-iodophenyl)propan-2-ol and 2.30 g. of DBU inCH₂Cl₂ (150 mL) while stirring at 0° C. under a nitrogen atmosphere. Thereaction was allowed to warm to room temperature and stirred overnightat this temperature. In the morning, the reaction was diluted withCH₂Cl₂ (100 mL) and the organic layer was washed two times with H₂O,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedvacuum to yield a viscous oil. This material was purified via silica gelchromatography employing the Chromatotron, using a 4000 micron rotor andeluting with a solvent of methylene chloride/methanol 19:1 to yield theintermediate title compound (1.0 g, 31%) as a viscous oil. Ion sprayM.S. 382 (M*−1).

Preparation of Final Title Compound

Scheme I, Step B: Into a 10 mL single neck flask, a solution of[2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (158 mg,0.41 mmol) in 1.7 mL CH₂Cl₂ was added syringe wise slowly to a solutionof DAST (66 mg, 0.41 mmol) in 0.3 mL CH₂Cl₂ while stirring at −78° C.under nitrogen. The reaction was then allowed to warm to roomtemperature and the mixture was diluted with H₂O and CH₂Cl₂. The layerswere separated and the organic layer was washed twice with H₂O, driedover anhydrous Na₂SO₄, filtered, and concentrated under reduced vacuumto provide the final title compound (113 mg) as a solid. Ion spray M.S.384 (M*−1).

Additional Preparation of Final Title Compound

Scheme I, step B: Into a 100 mL 3-neck flask fitted with a stirrer andthermometer, 1.0 g. of[2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine in CH₂Cl₂(15 mL) was added dropwise to 0.3 mL DAST in CH₂CL₂ (10 mL) whilestirring at −78° C. under a nitrogen atmosphere. Reaction was allowed towarm to room temperature and diluted with CH₂Cl₂ (50 mL). This organiclayer was washed with H₂O, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced vacuum to yield an oil. This material waspurified via silica gel chromatography employing the Chromatotron andusing a 4000 micron rotor while eluting with a gradient solvent ofhexane/ethyl acetate 9:1 to hexane/ethyl acetate 3:1 to yield the finaltitle compound (0.906 g) as a white solid. Ion spray M.S. 384 (M*−1).

Analysis for C₁₂H₁₇NO₂SFI:

Theory: C, 37.42 H, 4.44 N, 3.64 Found: C, 37.27 H, 4.33 N, 3.61

EXAMPLE 1a Preparation of(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine and(−)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine

[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (2.0 g,prepared in example 1) was dissolved into 3A ethanol (30 mL) and wasfurther diluted with heptane (20 mL). [As used herein the term “3Aethanol” refers to ethanol containing 5% methanol.] The mixture wasagitated via ultrasound to form a clear, colorless solution. This lotwas loaded upon a 8×28 cm preparative Chiralpak AD chromatographiccolumn that was pre-equilibrated with 60% 3A ethanol/40% heptane. Eluentflow was 300 mL/min and detection wavelength was 240 nm. The firsteluting substance was(+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine,[α]_(D)=+18.5 (c=1.08, MeOH), and the subsequent eluting substance was(−)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine,[α]_(D)=−23.5 (c=1.02, MeOH). The above procedure was repeated twice inan analogous manner with[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (secondrun, 3.0 g dissolved in 50 mL 3A ethanol/heptane, 3:2 and a third run,2.0 g dissolved in 0.8 g dissolved in 40 mL 3A ethanol/heptane, 3:2).Thus, in three runs, a total of 5.8 g of[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine wasresolved into its component enantiomers in the following yields afterconcentration (in vacuo) of fractions:

-   -   (+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine        (2.38 g, 41.0%);    -   (−)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine        (1.2 g, 20.7%).

Analysis conditions: 0.46×35 cm Chiralpak AD 60% ethanol (5%methanol)/40% Heptane; Flow: 1.0 mL/min, detection wavelength: 240 nm.

For (+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine:R_(t)=5.4 min, MS (ES+) 384 (M−1). ¹H NMR (CDCl₃, 300 MHz): δ 7.73 (d,2H, J=8.1), 7.09 (d, 2H, J=8.4), 4.27 (t, 1H, J=6.2), 3.50 (m, 2H), 3.03(m, 1H), 1.69 (d, 3H, J=22), 1.30 (d, 3H, J=7), 1.27 (d, 3H, J=7).Analysis for C₁₂H₁₇FINO₂S: Theory: C, 37.41; H, 4.45; N, 3.64. Found: C,37.54; H, 4.43; N, 3.64.

For (−)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine:R_(t)=10.1 min. MS (ES+) 384 (M−1). ¹H NMR spectrum identical to that of(+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine.Analysis for C₁₂H₁₇FINO₂S: Theory: C, 37.41; H, 4.45; N, 3.64. Found: C,37.56; H, 4.43; N, 3.59.

EXAMPLE 2 Preparation of[2-Fluoro-2-(4-phenylphenyl)propyl][(methylethyl)sulfonyl]amine

Scheme VI, Step A′: Into a 10 mL single neck flask was placed[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (113 mg,0.29 mmol, prepared in example 1), phenyl boric acid (54 mg, 0.44 mmol),potassium carbonate (61 mg, 0.44 mmol), and tetrakis(triphenylphosphine)Pd(0) (17 mg, 0.02 mmol) in a mixture of dioxane/water (3:1, 7mL). The mixture was then heated at 100° C. with stirring for 18 hours.The reaction was then cooled to room temperature and poured into H₂O.The mixture was extracted with EtOAc and the organic layer was washedtwice with H₂O, dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced vacuum. The resulting semi-solid was purified via radialchromatography (Chromatotron, Harrison Research Inc., 840 Moana Court,Palo Alto, Calif. 94306) using a 2000 micron rotor (silica gel) andeluting with a solvent of Hexane/EtOAc 4:1 to provide the title compound(33 mg, 34%) as a slowly crystallizing tan oil. Ion spray M.S. 335(M*+1).

Analysis for C₁₈H₂₂NO₂S:

Theory: C, 64.45 H, 6.61 N, 4.18 Found: C, 65.50 H, 6.46 N, 4.05

EXAMPLE 3 Preparation of4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenecarbonitrile

Preparation of 4-Cyanobenzene Boronic Acid

A solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) wasdried in the presence of activated 3 Å molecular sieves at room temp.This solution was filtered and cooled to −100° C. A 1.6 M solution ofn-butyllithium in hexanes (355 mL. 0.567 mol) was added to the coldsolution over 15 min while maintaining the internal temperature between−105 and −93° C. To the resulting orange reaction mixture was addedtrimethylborate (81 g, 0.78 mol) over 3 min, briefly increasing thereaction temperature to −72° C. The reaction mixture was recooled to−100° C. over 5 minutes and then was allowed to warm slowly to roomtemperature over 2.3 h. The reaction mixture was acidified with 4N HClto pH 2.2, and was diluted with CH₂Cl₂ (200 mL). The aqueous layer wasseparated and the organic layer was washed with brine (2×200 mL), driedover anhydrous MgSO₄, filtered, and the solvent removed under reducedpressure to a pale yellow solid. This solid was additionally purified bydissolution in 1N NaOH and extraction into CH₂Cl₂/THF (1:1, 2×200 mL).The aqueous phase was acidified with 4N HCl to pH 2.2 and was extractedinto CH₂Cl₂/THF (1:1, 500 mL). The combined organic extracts wereconcentrated to a crude solid (64.6 g) that was triturated with diethylether (160 mL) and dried under vacuum to afford the intermediate titlecompound (44.0 g, 59.9%) as a white powder. ¹H NMR (d₆-acetone, 300MHz): δ 8.03 (d, 2H, J=8.1), 7.75 (d, 2H, J=8.4), 7.54 (s, 2H).

Preparation of4-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenecarbonitrile

Scheme VI, Step A: Into a 50 mL single neck flask was placed2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (350 mg,0.90 mmol, intermediate prepared in example 1), 4-cyanobenzene boronicacid (206 mg, 1.40 mmol), potassium carbonate (193 mg, 1.40 mmol), andtetrakis(triphenyl phosphine)palladium(0) (52 mg, 0.045 mmol) indioxane/water (3:1, 25 mL), and the mixture was heated at 100° C. withstirring for 18 hours. The reaction was cooled to room temperature andpoured into H₂O. The reaction mixture was extracted with EtOAc and theorganic layer was separated and washed twice with H₂O, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced vacuum. Theresulting semi-solid was purified via radial chromatography(Chromatotron) using a 4000 micron rotor (silica gel) and eluting with asolvent of Hexane/EtOAc 3:1 to provide the intermediate title compound(265 mg, 82%) as a solid. Ion spray M.S. 357 (M*−1).

Analysis for C₁₉H₂₂N₂O₃S:

Theory: C, 63.66 H, 6.18 N, 7.81 Found: C, 63.26 H, 6.49 N, 7.67

Preparation of Final Title Compound

Scheme VI, Step B: Into a 25 mL single neck flask, a solution of4-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenecarbonitrile(253 mg, 0.70 mmol) in 8 mL CH₂Cl₂ was added syringe wise slowly to asolution of DAST (114 mg, 0.71 mmol) in 2 mL CH₂Cl₂ while stirring at−78° C. under an atmosphere of nitrogen. The reaction was then allowedto warm to room temperature and the mixture was diluted with H₂O andCH₂Cl₂. The layers were separated and the organic layer was washed twicewith H₂O, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced vacuum to provide the crude title compound as a solid. Thiscrude material was then purified via radial chromatography using a 2000micron rotor (silica gel) and eluting with a solvent of Hexane/EtOAc 3:1to provide the title compound (174 mg, 69%) as a white solid. m.p.123°–126° C. Ion spray M.S. 359 (M*−1).

Analysis for C₁₉H₂₁N₂O₂SF:

Theory: C, 63.31 H, 5.87 N, 7.77 Found: C, 62.72 H, 5.76 N, 7.72

EXAMPLE 4 Preparation of4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicAcid

Scheme VI, Step A′: Into a 50 mL single neck flask[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (300 mg,0.78 mmol, prepared in example 1), 4-carboxybenzene boronic acid (188mg, 1.13 mmol), potassium carbonate (156 mg, 1.13 mmol) andtetrakis(triphenyl phosphine)palladium(0) (52 mg, 0.05 mmol) werecombined in dioxane/water (30 mL, 3:1). The mixture was then heated at100° C. with stirring for 18 hours. The reaction was cooled to roomtemperature and poured into H₂O. The desired product was extracted withethyl acetate and the organic layer was separated, washed twice withH₂O, dried over K₂CO₃, and concentrated under reduced vacuum to yieldthe crude material (350 mg) as a tan solid. The crude material waspurified via silica gel chromatography employing the Chromatotron usinga 4000 micron rotor and eluting with a solvent of methylenechloride/methanol 9:1 to yield the title compound (91 mg, 31%) as awhite solid.

Ion spray M.S. 378 (M*−1)

EXAMPLE 4a Preparation of4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicAcid (Enantiomer 1)

(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (627mg, 3.8 mmol), potassium carbonate (520 mg, 3.8 mmol),tetrakis(triphenyl phosphine)palladium(0) (206 mg, 0.2 mmol) anddioxane/water (112 mL, 3:1) were mixed together in a 250 mL single neckflask and stirred at 80° C. for 4 hours. The reaction was cooled to roomtemperature and poured into 1N HCl and the desired product was extractedwith ethyl acetate. The organic layer was dried over MgSO₄, filtered,and concentrated under reduced pressure to yield 1.43 g as a dark oil.This material was purified via silica gel chromatography employing thechromatotron and using a 4000 micron rotor while eluting with a solventof methylene chloride/methanol 9:1 to yield the title compound (355 mg,36%) as a tan solid. Ion spray M.S. 378.3 (M*−1).

EXAMPLE 4b Preparation of4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicAcid (Enantiomer 2)

(−)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (485mg, 2.9 mmol), Na₂CO₃/H₂O (4.4 mL, excess), tetrakis(triphenylphosphine)palladium(0) (206 mg, 0.2 mmol) and dioxane (20 mL) were mixedtogether in a 50 mL single neck flask and stirred at 80° C. for 4 hours.The reaction was cooled to room temperature and poured into 1N HCl andthe desired product was extracted with ethyl acetate. The organic layerwas dried over MgSO₄, filtered, and concentrated under reduced pressureto yield 871 mg as a foam. This material was purified via silica gelchromatography employing the chromatotron and using a 4000 micron rotorwhile eluting with a solvent of methylene chloride/methanol 9:1 to yieldthe title compound (500 mg, 51%) as a tan solid. Ion spray M.S. 378.1(M*−1).

Calculated for: C₁₉H₂₂NO₄S F—H₂O:

Theory: C 57.41, H 6.09, N 3.52. Found: C 57.20, H 5.82, N 3.52.

EXAMPLE 5 Preparation of{2-[4-(3-Aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine

Scheme VI, Step A′: Into a 50 mL single neck flask[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg,0.53 mmol, prepared in example 1), 3-aminobenzene boronic acid (188 mg,0.76 mmol), potassium carbonate (104 mg, 0.76 mmol) andtetrakis(triphenyl phosphine)palladium(0) (41 mg, 0.036 mmol) werecombined in dioxane/water (20 mL, 3:1). The mixture was heated at 100°C. under stirring for 18 hours. The reaction was cooled to roomtemperature and poured into H₂O. The desired product was extracted withethyl acetate and the organic layer was separated and washed twice withH₂O, dried over K₂CO₃, and concentrated under reduced vacuum to yieldthe crude material (276 mg) as a dark oil. The resulting oil waspurified via silica gel chromatography employing the Chromatotron usinga 4000 micron rotor and eluting with a solvent of Hexane/Ethyl Acetate1:1 to yield the title compound (164 mg, 90%) as a viscous oil. Ionspray M.S. 351.4 (M*+1).

Analysis calculated for: C₁₈ H₂₃ N₂ O₂ S F:

Theory: C, 61.69 H, 6.62 N, 7.99 Found: C, 61.53 H, 6.55 N, 8.13

EXAMPLE 6 Preparation of[2-Fluoro-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine

A 50 mL flask fitted with a stirrer and thermometer was charged with DBU(67 mg, 1.1 eq),{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine(140 mg, 0.44 mmol, prepared in example 5) and methylene chloride (10mL) under an atmosphere of nitrogen, and cooled to 0° C. To thisstirring solution was added dropwise chloro-methane sulfonyl chloride(69 mg, 1.5 eq). The reaction was allowed to warm to room temperatureand stirred overnight at this temperature. In the morning, the mixturewas poured into H₂O and the layers were separated. The organic layer waswashed once with H₂O, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced vacuum to yield the crude material (192 mg)as a yellow oil. This crude material was purified via silica gelchromatography employing the Chromatotron using a 4000 micron rotor andeluting with a solvent of Methylene Chloride/ethyl acetate 9:1 to yieldthe title compound (50 mg, 29%) as a white foam. Ion spray mass spectra427.1 (M*−1).

Analysis for C₁₉ H₂₅ N₂ O₄ S₂ F:

Theory: C, 53.25 H, 5.88 N, 6.54 Found: C, 53.56 H, 6.11 N, 6.29

EXAMPLE 6a Preparation of[2-Fluoro-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine(Enantiomer 1)

(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (300mg, 0.78 mmol, prepared in example 1a), the borate of formula:

(347 mg, 1.5 eq.), potassium carbonate (156 mg, 1.5 eq),tetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.06 mmol) anddioxane/water (36 mL, 3:1) were mixed together in a 100 mL single neckflask and stirred at 80° C. for 4 hours. The reaction was cooled to roomtemperature and poured into H₂O and the desired product was extractedwith ethyl acetate. The organic layer was backwashed once with H₂O,dried over K₂CO₃, filtered, and concentrated under reduced pressure toyield 191 mg as a viscous oil. This material was purified via silica gelchromatography employing the chromatotron and using a 2000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 1:1 to yield thetitle compound (86 mg, 26%) as a white solid. Ion spray M.S. 427.1(M*−1).

Calculated for: C₁₉H₂₅N₂O₄S₂ F—H₂O:

Theory: C 51.08, H 6.09, N 6.27. Found: C 51.29, H 5.63, N 6.29.

EXAMPLE 6b Preparation of[2-Fluoro-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine(Enantiomer 2)

(−)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (493mg, 1.28 mmol, prepared in example 1a), the borate of formula:

(385 mg, 1.30 mmol), 2.0 M Na₂CO₃/H₂O (2.2 mL, excess),tetrakis(triphenyl phosphine)palladium(0) (100 mg, 0.09 mmol) anddioxane (15 mL) were mixed together in a 50 mL single neck flask andstirred at 80° C. overnight. In the morning the reaction was cooled toroom temperature and poured into H₂O and the desired product wasextracted with ethyl acetate. The organic layer was backwashed once withH₂O, dried over K₂CO₃, filtered, and concentrated under reduced pressureto yield 571 mg as a foam. This material was purified via silica gelchromatography employing the chromatotron and using a 4000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 1:1 to yield thetitle compound (294 mg, 56%) as a brown solid. Ion spray M.S. 427.3(M*−1).

Calculated for: C₁₉H₂₅N₂O₄S₂ F—H₂O: Theory: C, 51.08; H, 6.09; N, 6.27.Found: C, 51.29; H, 5.63; N, 6.29.

EXAMPLE 7 Preparation of[2-Fluoro-2-(4-(3-thienyl)phenyl)propyl][(methylethyl)sulfonyl]amine

Scheme VI, Step A′: Into a 50 mL single neck[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (150 mg,0.39 mmol, prepared in example 1), thiophene-3-benzene boronic acid (74mg, 0.56 mmol), potassium carbonate (80 mg, 0.56 mmol) andtetrakis(triphenyl phosphine)palladium(0) (31 mg, 0.027 mmol) werecombined in dioxane/water (15 mL, 3:1). The mixture was heated at 100°C. under stirring for 18 hours. The reaction was cooled to roomtemperature and poured into H₂O. The desired product was extracted withethyl acetate and the organic layer was separated and washed twice withH₂O, dried over K₂CO₃, and concentrated under reduced vacuum to yieldthe crude material (236 mg) as a dark oil. The resulting oil waspurified via silica gel chromatography employing the Chromatotron usinga 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate7:3 to yield the title compound (107 mg, 81%) as a white solid. Ionspray M.S. 340.0 (M*−1).

Analysis calculated for: C₁₆H₂₀NO₂S₂F:

Theory: C, 56.28 H, 5.90 N, 4.10 Found: C, 56.24 H, 5.86 N, 3.79.

EXAMPLE 8 Preparation of[2-Fluoro-2-(4-(3-pyridyl)phenyl)propyl][(methylethyl)sulfonyl]amine

Scheme VI, Step A′:[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg,0.52 mmol, prepared in example 1), pyridyl boronic acid (93 mg, 0.76mmol), potassium carbonate (104 mg, 0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.036 mmol), and dioxane/water (20 mL,3:1) were mixed together in a 100 mL single neck flask and stirred at90° C. over night. In the morning, the reaction was cooled to roomtemperature and poured into H₂O, and the desired product was extractedwith ethyl acetate. The organic layer was backwashed once with H₂O,dried over K₂CO₃, filtered, and concentrated under reduced pressure toyield 235 mg. of a viscous oil. This material was purified via silicagel chromatography employing the Chromatotron and using a 4000 micronrotor while eluting with a solvent of methylene chloride/ethyl acetate1:1 to yield the title compound (126 mg, 72%) as a semi-solid. Ion sprayM.S. 337.2 (M*+1).

Calculated for C₁₇H₂₁N₂O₂SF:

Theory: C 60.69, H 6.29, N 8.33. Found: C 60.86, H 6.17, N 7.99.

EXAMPLE 9 Preparation of2-{4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}ethanenitrile

Scheme VI, step A′:[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (500 mg,1.3 mmol, prepared in example 1), 4-phenylacetonitrile boronic acid (193mg, 1.4 mmol), potassium carbonate (193 mg, 1.4 mmol),tetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.65 mmol),dioxane/water (30 mL, 3:1) were mixed together in a 100 mL single neckflask and stirred at 90° C. over night. In the morning, the reaction wascooled to room temperature and poured into H₂O and the desired productwas extracted with ethyl acetate. The organic layer was backwashed oncewith H₂O, dried over K₂CO₃, and concentrated under reduced pressure toyield a viscous oil. This material was purified via silica gelchromatography employing the Chromatotron and using a 2000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 7:3 to yield thetitle compound (143 mg, 30%) as a yellow solid. Material wasrecrystallized from ethyl acetate-hexane 1:1. M.P. 155°–157° C. Ionspray M.S. 373 (M*−1).

Calculated for C₂₀H₂₃N₂O₂SF:

Theory: C 64.15, H 6.19, N 7.48. Found: C 63.91, H 5.96, N 7.37.

EXAMPLE 10 Preparation of4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzaldehyde

Preparation of4-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzaldehyde

Scheme VI, step A:[2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.05 g,2.7 mmol, intermediate prepared in example 1), 4-formylphenyl boronicacid (564 mg, 3.5 mmol), potassium carbonate (483 mg, 3.5 mmol),tetrakis(triphenyl phosphine)palladium(0) (162 mg, 1.4 mmol), anddioxane/water (60 mL, 3:1) were mixed together in a 250 mL single neckflask and stirred at 90° C. over night. In the morning, the reaction wascooled to room temperature and poured into H₂O and the desired productwas extracted with ethyl acetate. The organic layer was backwashed oncewith H₂O, dried over K₂CO₃, and concentrated under reduced pressure toyield a viscous oil. This material was purified via silica gelchromatography employing the Chromatotron and using a 2000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 1:1 to yield thetitle compound as a pale yellow solid. This material was recrystallizedfrom ethyl acetate-hexane 1:1 to yield the intermediate title compound(519 mg) as a solid. Ion spray M.S. 360 (M*−1).

Calculated for C₁₉H₂₃NO₄S:

Theory: C 63.13, H 6.41, N 3.87. Found: C 62.94, H 6.29, N 3.82.

Preparation of Final Title Compound

Scheme VI, step B: Into a 250, 3 neck flask fitted with a stirrer andthermometer,4-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzaldehyde(519 mg) in CH₂Cl₂ (25 mL) was added dropwise to 0.19 mL DAST in CH₂CL₂(35 mL) while stirring at −78° C. under a nitrogen atmosphere. Reactionwas allowed to warm to room temperature and diluted with CH₂Cl₂ (75 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, filtered, andconcentrated under reduced vacuum to yield an oil. This two spotmaterial was purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor while eluting with a solventof hexane/ethyl acetate 3:1 to provide the final title compound (0.337g, 66%, bottom spot) as a white solid. Ion spray M.S. 362 (M*−1).

Calculated for C₁₉ H₂₂ N O₃ S F:

Theory: C 62.79, H 6.10, N 3.85. Found: C 65.22, H 6.13, N 3.21.

EXAMPLE 11 Preparation of{4-[4-(1-Fluoro-1-methyl-2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide

Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringewise to4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid (150 mg, 0.40 mmol, prepared in example 4) in CH₂Cl₂ (10 mL) whilestirring under nitrogen at room temperature. Immediately, 1 drop of DMFwas added by pipette initiating a foaming of the mixture. The reactionwas stirred one hour at this temperature and then concentrated underreduced vacuum to yield a white semi-solid. This material was placedinto THF (10 mL) and added dropwise to a stirring solution of 40%methylamine in water (5 mL) at room temperature and the mixture wasstirred overnight. In the morning, the solution was concentrated underreduced vacuum and the resulting oil was taken into CH₂Cl₂ and theorganic layer was washed once with H₂O, dried over K₂CO₃, andconcentrated under reduced vacuum to yield 159 mg as a semi-solid. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor while eluting with a solventof methylene chloride/ethyl acetate 1:1 to yield the title compound (51mg, 32%) as a white solid. Ion spray M.S. 393.1 (M*+1).

Calculated for C₂₀H₂₅N₂O₃SF:

Theory: C 61.21, H 6.42, N 7.14. Found: C 59.92, H 5.86, N 6.84.

EXAMPLE 11a Preparation of{4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide(Enantiomer 1)

Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringewise to(+)-4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid (300 mg, 0.79 mmol, prepared in example 1a) in CH₂Cl₂ (20 mL) whilestirring under nitrogen at room temperature. Immediately, 1 drop of DMFwas added by pipette initiating a foaming of the mixture. The reactionwas stirred one hour at this temperature and then concentrated underreduced vacuum to yield a white semi-solid. This material was placedinto dioxane (20 mL) and added dropwise to a stirring solution of 40%methylamine (5 mL) at room temperature and the mixture was stirredovernight. In the morning, the solution was concentrated under reducedvacuum and the resulting oil was taken into methylene chloride and theorganic layer was washed once with H₂O, dried over K₂CO₃, filtered, andconcentrated under reduced vacuum to yield 271 mg as a semi-solid. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor while eluting with a solventof methylene chloride/ethyl acetate 1:1 to yield the title compound (100mg, 32%) as a white solid. Ion spray M.S. 391.2 (M*−1).

Calculated for C₂₀H₂₅N₂O₃SF—½H₂O:

Theory: C 59.82, H 6.52, N 6.98. Found: C 59.69, H 6.29, N 6.81.

EXAMPLE 11b Preparation of{4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide(Enantiomer 2)

Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringewise to(−)-4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid (300 mg, 0.79 mmol, prepared in example 1a) in methylene chloride(15 mL) while stirring under nitrogen at room temperature. Immediately,1 drop of DMF was added by pipette initiating a foaming of the mixture.The reaction was stirred one hour at this temperature and thenconcentrated under reduced vacuum to yield a white semi-solid. Thismaterial was placed into dioxane (20 mL) and added dropwise to astirring solution of 40% methylamine (5 mL) at room temperature and themixture was stirred overnight. In the morning, the solution wasconcentrated under reduced vacuum and the resulting oil was taken intomethylene chloride and the organic layer was washed once with H₂O, driedover K₂CO₃, filtered, and concentrated under reduced vacuum to yield 391mg as a solid. This material was purified via recrystallization fromhexane/ethyl acetate 1:1 to yield the title compound (231 mg, 49%) as awhite solid. Ion spray M.S. 391.4 (M*−1).

Calculated for C₂₀H₂₅N₂O₃SF—½H₂O:

Theory: C 59.82, H 6.52, N 6.98. Found: C 59.78, H 6.53, N 6.89.

EXAMPLE 12 Preparation of{4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N,N-dimethylcarboxamide

Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringewise to4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid (150 mg, 0.40 mmol, prepared in example 4) in CH₂Cl₂ (10 mL) whilestirring under nitrogen at room temperature. Immediately, 1 drop of DMFwas added by pipette initiating a foaming of the mixture. The reactionwas stirred one hour at this temperature and then concentrated underreduced vacuum to yield a white semi-solid. This material was placedinto THF (10 mL) and added dropwise to a stirring solution of 40%dimethylamine in water (5 mL) at room temperature and the mixture wasstirred overnight. In the morning, the solution was concentrated underreduced vacuum and the resulting oil was taken into CH₂Cl₂ and theorganic layer was washed once with H₂O, dried over K₂CO₃, andconcentrated under reduced vacuum to yield 167 mg as an oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor while eluting with a solventof methylene chloride/ethyl acetate 1:1 to yield the title compound (97mg, 60%) as a viscous oil. Ion spray M.S. 407.4 (M*+1).

Calculated for C₂₁H₂₇N₂O₃SF:

Theory: C 62.05, H 6.70, N 6.89. Found: C 61.32, H 6.69, N 6.85.

EXAMPLE 13 Preparation ofN-ethyl{4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}carboxamide

Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringewise to4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid (140 mg, 0.37 mmol, prepared in example 4) in CH₂Cl₂ (10 mL) whilestirring under nitrogen at room temperature. Immediately, 1 drop of DMFwas added by pipette initiating a foaming of the mixture. The reactionwas stirred one hour at this temperature and then concentrated underreduced vacuum to yield a white semi-solid. This material was placedinto THF (10 mL) and added dropwise to a stirring solution of 2.0 Methylamine in THF (0.5 mL) at room temperature and the mixture wasstirred overnight. In the morning, the solution was concentrated underreduced vacuum and the resulting oil was taken into CH₂Cl₂ and theorganic layer was washed once with H₂O, dried over K₂CO₃, andconcentrated under reduced vacuum to yield 151 mg as an oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor while eluting with a solventof methylene chloride/ethyl acetate 1:1 to yield the title compound (127mg, 85%) as a viscous oil. Ion spray M.S. 407.4 (M*+1).

EXAMPLE 14 Preparation of4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenylPyrrolidinyl Ketone

Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringewise to4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid (200 mg, 0.53 mmol, prepared in example 4) in CH₂Cl₂ (15 mL) whilestirring under nitrogen at room temperature. Immediately, 1 drop of DMFwas added by pipette initiating a foaming of the mixture. The reactionwas stirred one hour at this temperature and then concentrated underreduced vacuum to yield a white semi-solid. This material was placedinto THF (10 mL) and added dropwise to a stirring solution of 94 mgpyrolline in THF (10 mL) at room temperature and the mixture was stirredovernight. In the morning, the solution was concentrated under reducedvacuum and the resulting oil was taken into CH₂Cl₂ and the organic layerwas washed once with H₂O, dried over K₂CO₃, and concentrated underreduced vacuum to yield 271 mg as an oil. This material was purified viasilica gel chromatography employing the Chromatotron and using a 4000micron rotor while eluting with a solvent of hexane/ethyl acetate 7:3 toyield the title compound (141 mg, 62%) as a viscous oil. Ion spray M.S.433.3 (M*+1).

Calculated for C₂₃H₂₉N₂O₃SF:

Theory: C 63.86, H 6.76, N 6.48. Found: C 62.93, H 6.40, N 5.95.

EXAMPLE 15 Preparation ofN-{3-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}acetamide

Into a 100 mL single-neck flask, 49 mg of acetyl chloride was addeddropwise to 200 mg of{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine(prepared in example 5) and 63 mg of triethylamine in THF (25 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 193 mg as a foam.This material was purified via silica gel chromatography employing theChromatotron, using a 4000 micron rotor and eluting with a solvent ofhexane/ethyl acetate 1:1 to yield the title compound (121 mg, 54%) as awhite foam. Ion spray M.S. 391.2 (M*−1).

Calculated for: C₂₀H₂₅N₂O₃SF:

Theory: C 61.20, H 6.42, N 7.13. Found: C 60.28, H 6.40, N 6.76.

EXAMPLE 16 Preparation ofN-{3-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}propanamide

Into a 100 mL single-neck flask, 58 mg of propynyl chloride was addeddropwise to 200 mg of{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine(prepared in example 5) and 63 mg of triethylamine in THF (25 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 256 mg as a foam.This material was purified via silica gel chromatography employing theChromatotron, using a 4000 micron rotor and eluting with a solvent ofhexane/ethyl acetate 1:1 to yield the title compound (130 mg, 56%) as awhite foam. Ion spray M.S. 405.5 (M*−1).

Calculated for: C₂₁H₂₇N₂O₃SF—½H₂O:

Theory: C 60.69, H 6.79, N 6.74. Found: C 60.95, H 6.49, N 6.77.

EXAMPLE 17 Preparation ofN-{3-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}butanamide

Into a 100 mL single-neck flask, 71 mg of butyryl chloride was addeddropwise to 200 mg{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine(prepared in example 5) and 63 mg of triethylamine in THF (25 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 211 mg as an oil.This material was purified via silica gel chromatography employing theChromatotron, using a 4000 micron rotor and eluting with a solvent ofhexane/ethyl acetate 1:1 to yield the title compound (130 mg, 54%) as awhite foam. Ion spray M.S. 419.2 (M*−1).

Calculated for: C₂₂H₂₉N₂O₃SF:

Theory: C 62.83, H 6.95, N 6.66. Found: C 62.49, H 6.84, N 6.60.

EXAMPLE 18 Preparation ofAmino-N-{3-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}amide

Into a 100-single neck flask, 0.1 mL of TFA in toluene (5 mL) was addeddropwise to 200 mg{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine(prepared in example 5) and 56 mg of sodium cyanate in toluene (15 mL)while stirring under a nitrogen atmosphere at 45°–50° C. The reactionwas then heated to 80° C. for 1 h. The solution was cooled to roomtemperature and concentrated under reduced vacuum to yield a solid. ThisTFA salt was liberated with 1N NaOH and the desired product wasextracted into methylene chloride. The organic layer was backwashed oncewith H₂O, dried over K₂CO₃, and concentrated under reduced vacuum toyield 168 mg as a foam. This material was purified via silica gelchromatography employing the Chromatotron, using a 4000 micron rotor andeluting with a solvent of hexane/ethyl acetate 1:9 to yield the titlecompound (77 mg, 34%) as a yellow foam. Ion spray M.S. 392.2 (M*−1).

Calculated for: C₁₉H₂₄N₃O₃SF—H₂O:

Theory: C 55.45, H 6.37, N 10.21. Found: C 55.82, H 6.02, N  9.91.

EXAMPLE 19 Preparation ofN-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzamide

Preparation of[2-Hydroxy-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine

In a 500 mL, 3 neck flask fitted with a stirrer and thermometer, 2.98 g.of propanesulfonyl chloride was added dropwise to 3.92 g. of2-hydroxy-2-(4-nitrophenyl)propylamine and 3.19 g. of DBU in CH₂Cl₂ (200mL) while stirring at 0° C. under a nitrogen atmosphere. The reactionwas allowed to warm to room temperature and stirred overnight at thistemperature. In the morning, reaction was diluted with CH₂Cl₂ (100 mL)and the organic layer was washed two times with H₂O, dried over Na₂SO₄,and concentrated under reduced vacuum to yield a viscous oil. Thismaterial was purified via silica gel chromatography employing theWater's Prep 2000 and eluting with a solvent of hexane/ethyl acetate 1:1to yield the intermediate title compound (940 mg, 16%) as a viscous oil.Ion spray M.S. 302.1 (M*−1).

Preparation of[2-(4-Aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine

900 mg of[2-hydroxy-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine and 1.2equivalence of 10% Pd/C in ethyl acetate (50 mL) were subjected to ahydrogen atmosphere while shaking at 60 psi for 3 hours. Solution wasfiltered through a Celite® mat and the resulting filtrate wasconcentrated under reduced vacuum to yield 720 mg as an oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 4000 micron rotor while eluting with a solventof hexane/ethyl acetate 1:1 to yield the intermediate title compound(340 mg, 42%) as a tan solid. Ion spray M.S. 271.4 (M*−1).

Calculated for C₁₂H₂₀N₂O₃S:

Theory: C 52.92, H 7.40, N 10.29 Found: C 53.26, H 7.40, N 10.11

Preparation ofN-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzamide

Scheme XII, Step A: Into a 100 mL single-neck flask, 77 mg of benzoylchloride was added dropwise to 135 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine and 56mg of triethylamine in THF (20 mL) while stirring under a nitrogenatmosphere at room temperature. The reaction was allowed to stir at thistemperature for 2 h. The mixture was then poured into H₂O and thedesired product was extracted into ethyl acetate. The organic layer wasbackwashed once with H₂O, dried over K₂CO₃, and concentrated underreduced vacuum to yield 233 mg as a solid. This material was purifiedvia silica gel chromatography employing the Chromatotron, using a 2000micron rotor and eluting with a solvent of ethyl acetate to yield theintermediate title compound (151 mg, 80%) as a white solid. Ion sprayM.S. 375.2 (M*−1).

Preparation of Final Title Compound

Scheme XII, Step B: Into a 50 mL 3 neck flask fitted with a stirrer andthermometer, 130 mg ofN-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzamidein methylene chloride (5 mL) was added dropwise to 62 mg of DAST inmethylene chloride (5 mL) while stirring at −78° C. under a nitrogenatmosphere. Reaction was allowed to warm to room temperature and dilutedwith methylene chloride (25 mL). This organic layer was washed with H₂O,dried over Na₂SO₄, and concentrated under reduced vacuum to yield 136 mgas a white foam. This material was purified via silica gelchromatography employing the Chromatotron and using a 2000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 1:1 to yield thefinal title compound (79 mg, 60%) as a white solid. Yield=60%. Ion sprayM.S. 377.4 (M*−1).

Calculated for C₁₉ H₂₃N₂O₃SF:

Theory: C 60.30, H 6.13, N 7.31. Found: C 60.20, H 6.05, N 7.30.

EXAMPLE 20 Preparation of(3-Cyanophenyl)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Preparation of(3-Cyanophenyl)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Scheme XII, Step A: Into a 100 mL single-neck flask, 91 mg of3-cyanobenzoyl chloride was added dropwise to 135 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 56 mg of triethylamine in THF (20 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 254 mg as a solid.This material was purified via silica gel chromatography employing theChromatotron, using a 2000 micron rotor and eluting with a solvent ofethyl acetate to yield the intermediate title compound (131 mg, 66%) asan oil. Ion spray M.S. 400.1 (M*−1).

Calculated for: C₂₀H₂₃N₃O₄S:

Theory: C 59.83, H 5.77, N 10.47. Found: C 61.33, H 5.64, N 10.19.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 50 mL 3 neck flask fitted with a stirrer andthermometer, 110 mg of(3-cyanophenyl)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamidein methylene chloride (5 mL) was added dropwise to 48 mg of DAST inmethylene chloride (5 mL) while stirring at −78° C. under a nitrogenatmosphere. Reaction was allowed to warm to room temperature and dilutedwith methylene chloride (25 mL). This organic layer was washed with H₂O,dried over Na₂SO₄, and concentrated under reduced vacuum to yield 110 mgas a tan solid. This material was purified via silica gel chromatographyemploying the Chromatotron and using a 2000 micron rotor while elutingwith a solvent of hexane/ethyl acetate 1:1 to yield the final titlecompound (62 mg, 62%) as a yellow solid. Ion spray M.S. 402.2 (M*−1).

Calculated for C₂₀H₂₂N₃O₃SF: Theory: C, 59.54; H, 5.49; N, 10.41. Found:C, 58.74; H, 5.29; N, 10.03.

EXAMPLE 21 Preparation ofN-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-4-pyridylcarboxamide

Preparation ofN-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-4-pyridylcarboxamide

Scheme XII, Step A:[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine (350 mg,1.3 mmol, prepared in example 19), isonicotinic acid (176 mg, 1 mmol),triethylamine (333 mg, 3.3 mmol), 4-dimethylamino pyridine (12.2 mg,DMAP), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (298 mg,1.6 mmol, DCC) were mixed together with methylene chloride (15 mL) in a50 mL single neck flask and stirred under a nitrogen atmosphere at roomtemperature for 64 hours. The solution was then poured into H₂O, and thedesired product was extracted with ethyl acetate. The organic layer wasbackwashed once with H₂O, dried over K₂CO₃, and concentrated underreduced vacuum to yield 471 mg as an oil. This material was purified viasilica gel chromatography employing the Chromatotron, using a 4000micron rotor and eluting with a solvent of methylene chloride/methanol19:1 to yield the intermediate title compound (131 mg, 27%) as an oil.Ion spray M.S. 378.5 (M*+1).

Calculated for: C₁₈H₂₃N₃O₄S:

Theory: C 57.27, H 6.14, N 11.13. Found: C 57.75, H 5.97, N 11.05.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 50 mL 3 neck flask fitted with a stirrer andthermometer, 80 mg ofN-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-4-pyridylcarboxamidein methylene chloride (5 mL) was added dropwise to 0.1 mL of DAST inmethylene chloride (5 mL) while stirring at −78° C. under a nitrogenatmosphere. Reaction was allowed to warm to room temperature and dilutedwith methylene chloride (25 mL). This organic layer was washed with H₂O,dried over Na₂SO₄, and concentrated under reduced vacuum to yield 62.2mg as a yellow solid. This material was purified via silica gelchromatography employing the Chromatotron and using a 1000 micron rotorwhile eluting with a solvent of ethyl acetate to yield the final titlecompound (32 mg, 40%) as a pale yellow solid. Ion spray M.S. 380.4(M*+1).

Calculated for C₁₈H₂₂N₃O₃SF—½H₂O:

Theory: C 55.56, H 5.96, N 10.81. Found: C 55.40, H 5.73, N 10.41.

EXAMPLE 22 Preparation ofN-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]{4-[2-(methoxycarbonylamino)ethyl]phenyl}carboxamide

Preparation of N-[2-(4-Bromophenyl)ethyl]methoxycarboxamide

Into a 50 mL-single neck flask, 260 mg of methyl chloroformate inacetone (5 mL) was added dropwise to 500 mg of 4-bromophenethyl amineand 291 mg of Na₂CO₃ in acetone (20 mL) while stirring at roomtemperature under a nitrogen atmosphere. The reaction was then stirredovernight at this temperature. In the morning, the mixture was pouredinto H₂O and the desired product was extracted with ethyl acetate. Thisorganic layer was washed with H₂O, dried over Na₂SO₄, and concentratedunder reduced vacuum to yield the intermediate title compound (714 mg)as a white solid. This material was taken to the next reaction withoutfurther purification. Ion spray M.S. 259.2 (M*+1).

Preparation of Final Title Compound

Into a 100 mL-single neck flask, 285 mg of[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (preparedin example 1), 200 mg of 4,4,5,5-tetramethyl-1,2,3-dioxaborolane(Dibron), and 215 mg of potassium acetate in DMF (15 mL) was stirred anddegassed with argon for 10 minutes. Then, 15 mg of PdCl₂(dppf) was addedportion wise and the reaction was stirred at 80° C. under a nitrogenatmosphere for 2 hours. The reaction was then cooled to room temperatureand 3.40 mg of N-[2-(4-bromophenyl)ethyl]methoxycarboxamide, 1.80 mLNa₂SO₃/H₂O, and an additional 15 mg of PdCl₂(dppf) was added all portionwise and the mixture was then heated to 80° C. and stirred overnight. Inthe morning, the mixture was cooled to room temperature and poured intoH₂O and the desired product was extracted with ethyl acetate. Thisorganic layer was washed with H₂O, dried over Na₂SO₄, and concentratedunder reduced vacuum to yield 616 mg of a dark oil. This two spotmaterial was purified via silica gel chromatography employing theChromatotron and using a 4000 micron rotor while eluting with a solventof methylene chloride/ethyl acetate 9:1. Collection of the bottom spotprovided the final title compound (55 mg, 17%) as a slowly crystallizingoil. Ion spray M.S. 435.3 (M*−1).

Calculated for: C₂₂H₂₉N₂O₄SF:

Theory: C 60.53, H 6.70, N 6.42. Found: C 60.52, H 6.77, N 6.06.

EXAMPLE 23 Preparation of(2-{4-[(3,5-Difluorophenyl)methoxy]phenyl}-2-fluoropropyl)[(methylethyl)sulfonyl]amine

Preparation of[2-Hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine

Into a 50 mL-3 neck flask fitted with a stirrer and thermometer wasplaced 1.0 gm. Of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 4.06 gm of 48% HBF₄ in H₂O (20 mL) at 0° C.The reaction was then stirred at this temperature for 30 minutes. 0.26gm of sodium nitrite was then added portion wise to the mixture andstirring at this temperature continued for an additional 30 minutes. Thereaction was then slowly heated to 70° C. and stirred at thistemperature for 3 hours. The mixture was cooled to room temperature andthe solution was taken to pH 12 with 1 N NaOH and the solution wasfiltered. The filtrate was the taken to pH 3.0 with 1 N HCl and thedesired product was extracted into ethyl acetate. The organic layer wasdried over Na₂SO₄, and concentrated under reduced vacuum to yield 1.20gm of a dark oil. This two spot material was purified via silica gelchromatography employing the Chromatotron and using a 4000 micron rotorwhile eluting with a solvent of methylene chloride/ethyl acetate 9:1.Collection of the bottom spot provided the intermediate title compound(200 mg, 20%) as a slowly crystallizing oil. Ion spray M.S. 272.4(M*−1).

Preparation of(2-{4-[(3,5-Difluorophenyl)methoxy]phenyl}-2-hydroxypropyl)[(methylethyl)sulfonyl]amine

Scheme XI, Step A: Into a 100 mL-3 neck flask fitted with a stirrer andthermometer, 200 mg of[2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF(5 mL) was added dropwise to 35 mg of NaH in DMF (20 mL) while stirringat room temperature under a nitrogen atmosphere. After stirring at thistemperature for 30 minutes, 153 mg of 3,5-difluorobenzyl bromide in DMF(5 mL) was added dropwise followed by the addition of 92 mg of NaIportion wise. The reaction was then heated at 100° C. for 2 hours. Themixture was cooled to room temperature and poured into H₂O and thedesired product was extracted with ethyl acetate. This organic layer waswashed with H₂O, dried over K₂CO₃, and concentrated under reduced vacuumto yield 410 mg of a brown oil. This two spot material was purified viasilica gel chromatography employing the Chromatotron and using a 4000micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1.Collection of the bottom spot provided the intermediate title compound(70 mg, 24%) as an oil. Ion spray M.S. 398.1 (M*−1).

Preparation of Final Title Compound

Scheme XI, Step B: Into a 25-3 neck flask fitted with a stirrer andthermometer, 70 mg of(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxypropyl)[(methylethyl)sulfonyl]aminein methylene chloride (5 mL) was added dropwise to 0.1 mL DAST inmethylene chloride (5 mL) while stirring at −78° C. under a nitrogenatmosphere. The reaction was allowed to warm to room temperature anddiluted with methylene chloride (25 mL). This organic layer was washedwith H₂O, dried over Na₂SO₄, and concentrated under reduced vacuum toyield 64 mg of an oil. This material was purified via silica gelchromatography employing the Chromatotron and using a 1000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 1:1 to provide thefinal title compound (45 mg, 63%) as an orange oil. Ion spray M.S. 401.3(M*).

EXAMPLE 24 Preparation of{2-Fluoro-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine

Preparation of{2-Hydroxy-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine

Scheme VI, Step A:[2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (383 mg,100 mmol, intermediate prepared in example 1),BOC-4-(ethyl)methyl-phenyl boronic acid (688 mg, 200 mmol), potassiumcarbonate (276 mg, 200 mmol), tetrakis(triphenyl phosphine)palladium(0)(58 mg, 0.05 mmol), and dioxane/water (60 mL, 3:1) were mixed togetherin a 250 mL single neck flask and stirred at 90° C. over night. In themorning, the reaction was cooled to room temperature and poured into H₂Oand the desired product was extracted with ethyl acetate. The organiclayer was backwashed once with H₂O, dried over K₂CO₃, and concentratedunder reduced pressure to yield a 3 spot material as a viscous oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 4000 micron rotor while eluting with a solventof hexane/ethyl acetate 7:3 to yield the intermediate title compound(383 mg, 72%, bottom spot) as an oil. Ion spray M.S. 453 (M*−1).

Calculated for C₂₁H₃₀N₂O₅S₂:

Theory: C 55.48, H 6.65, N 6.16. Found: C 55.11, H 6.48, N 6.04.

Preparation of Final Title Compound

Scheme VI, Step B: Into a 50-3 neck flask fitted with a stirrer andthermometer, 383 mg of{2-hydroxy-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]aminein methylene chloride (5 mL) was added dropwise to 0.1 mL DAST inmethylene chloride (20 mL) while stirring at −78° C. under a nitrogenatmosphere. The reaction was allowed to warm to room temperature anddiluted with methylene chloride (50 mL). This organic layer was washedwith H₂O, dried over Na₂SO₄, and concentrated under reduced vacuum toyield an oil. This material was purified via silica gel chromatographyemploying the Chromatotron and using a 2000 micron rotor while elutingwith a solvent of hexane/ethyl acetate 1:1 to yield the final titlecompound (228 mg, 56%) as an oil. Ion spray M.S. 455 (M*−1).

Calculated for C₂₁H₂₉N₂O₄S₂F:

Theory: C 55.24, H 6.41, N 6.13. Found: C 55.05, H 6.41, N 6.10.

EXAMPLE 25 Preparation of(4-Chlorophenyl)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Preparation of(4-Chlorophenyl)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Scheme XII, Step A: Into a 100 mL single-neck flask, 142 mgof4-chlorobenzoyl chloride was added dropwise to 200 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 83 mg of triethylamine in THF (25 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 310 mg as a whitesolid. This material was purified via recrystallization fromhexane-ethyl acetate 1:1 to yield intermediate title compound (165 mg,54%) as a white solid. Ion spray M.S. 409.2 (M*31 1).

Calculated for C₁₉ H₂₃ N₂ O₄ S Cl:

Theory: C 55.53, H 5.64, N 6.82. Found: C 55.33, H 5.47, N 6.75.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 100 mg of(4-chlorophenyl)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamidein CH₂Cl₂ (5 mL) was added dropwise to 0.03 mL DAST in CH₂CL₂ (5 mL)while stirring at −78° C. under a nitrogen atmosphere. Reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 108 mg as a foam. Thismaterial was triturated in hexane/ethyl acetate 19:1 for ½ h and thenfiltered to yield the final title compound (90 mg, 87%) as a tan solid.Ion spray M.S. 413.1 (M*).

Calculated for: C₁₉H₂₂N₂O₃SFCl—½H₂O:

Theory: C 54.08, H 5.49, N 6.64. Found: C 53.91, H 5.28, N 6.75.

EXAMPLE 26 Preparation of(6-Chloro(3-pyridyl))-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Preparation of(6-Chloro(3-pyridyl))-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Scheme XII, Step A: Into a 100 mL single-neck flask, 142 mg of6-chloronicotinoyl chloride was added dropwise to 200 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 83 mg of triethylamine in THF (25 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 294 mg as a whitesolid. This material was purified via recrystallization from ethylacetate to yield the intermediate title compound (161 mg, 53%) as awhite solid. Ion spray M.S. 412.1 (M*−1).

Calculated for C₁₈ H₂₂ N₃ O₄ S Cl:

Theory: C 52.49, H 5.38, N 10.20. Found: C 51.94, H 5.20, N 9.87.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 25-3n flask fitted with a stirrer andthermometer, 100 mg of(6-chloro(3-pyridyl))-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamidein CH₂Cl₂ (5 mL) was added dropwise to 0.03 mL DAST in CH₂CL₂ (5 mL)while stirring at −78° C. under a nitrogen atmosphere. Reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 118 mg as a foam. Thismaterial was triturated in hexane/ethyl acetate 19:1 for ½ h and thenfiltered to yield the final title compound (80 mg, 81%) as a whitesolid. Ion spray M.S. 414.1 (M*).

Calculated for: C₁₈H₂₁N₃O₃SFCl:

Theory: C 52.23, H 5.11, N 10.15. Found: C 52.49, H 5.26, N 9.75.

EXAMPLE 27 Preparation of(4-Cyanophenyl)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Preparation of(4-Cyanophenyl)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Scheme XII, Step A: Into a 100 mL single-neck flask, 135 mg of4-cyanobenzoyl chloride was added dropwise to 200 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 83 mg of triethylamine in THF (25 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 294 mg as a whitesolid. This material was purified via recrystallization from ethylacetate/hexane 2:1 to yield intermediate title compound (131 mg, 55%) asa white solid. Ion spray M.S. 400.2 (M*−1).

Calculated for C₂₀ H₂₃ N₃ O₄ S:

Theory: C 59.83, H 5.77, N 10.46. Found: C 59.00, H 5.53, N 10.27.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 100 mg of(4-cyanophenyl)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamidein CH₂Cl₂ (5 mL) was added dropwise to 0.03 mL DAST in CH₂CL₂ (5 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 107 mg as a yellow solid.This material was triturated in hexane/ethyl acetate 19:1 for ½ h andthen filtered to yield the final title compound (65 mg, 65%) as a tansolid. Ion spray M.S. 404.1 (M*+1).

Calculated for: C₂₀H₂₂N₃O₃SF—½H₂O:

Theory: C 58.23, H 5.62, N 10.18. Found: C 58.36, H 5.37, N 10.16.

EXAMPLE 28 Preparation ofEthoxy-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Preparation ofEthoxy-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide

Scheme XII, Step A: Into a 100 mL single-neck flask, 89 mg of ethylchloroformate was added dropwise to 200 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 83 mg of triethylamine in THF (25 mL) whilestirring under a nitrogen atmosphere at room temperature. The reactionwas allowed to stir at this temperature for 2 h. The mixture was thenpoured into H₂O and the desired product was extracted into ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced vacuum to yield 317 mg as an oil.This material was purified via silica gel chromatography employing theChromatotron while using a 4000 micron rotor and eluting with anisocratic solvent of methylene chloride/ethyl acetate 7:3 to yieldintermediate title compound (200 mg, 78%) as a viscous oil. Ion sprayM.S. 343.2 (M*−1).

Calculated for C₁₅ H₂₄ N₂ O₅ S:

Theory: C 52.30, H 7.02, N 8.13. Found: C 52.01, H 6.98, N 7.95.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 25 mL, 3 neck flask fitted with a stirrer andthermometer, 175 mg ofethoxy-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamidein CH₂Cl₂ (5 mL) was added dropwise to 0.04 mL DAST in CH₂CL₂ (10 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 181 mg as an oil. Thismaterial was purified via silica gel chromatography employing theChromatotron, using a 2000 micron rotor and eluting with a solvent ofhexane/ethyl acetate 7:3 to yield the final title compound (101 mg, 57%)as a viscous oil. Ion spray M.S. 345.1 (M*−1).

Calculated for: C₁₅H₂₃N₂O₄SF:

Theory: C 52.01, H 6.69, N 8.09. Found: C 51.82, H 6.64, N 8.22.

EXAMPLE 29 Preparation ofN-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]isoxazol-5-ylcarboxamide

Preparation ofN-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]isoxazol-5-ylcarboxamide

Scheme XII, Step A: Into a 100 mL single-neck flask, 159 mg ofisoxazole-5-carbonyl chloride was added dropwise to 300 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 122 mg of triethylamine in THF (35 mL)while stirring under a nitrogen atmosphere at room temperature. Thereaction was allowed to stir at this temperature for 2 h. The mixturewas then poured into H₂O and the desired product was extracted intoethyl acetate. The organic layer was backwashed once with H₂O, driedover K₂CO₃, and concentrated under reduced vacuum to yield 416 mg as asolid. This material was purified via recrystallization from ethylacetate/hexane 1:1 to yield intermediate title compound (207 mg, 51%) asa white solid. Ion spray M.S. 366.1 (M*−1).

Calculated for C₁₆ H₂₁ N₃ O₅ S

Theory: C 52.30, H 5.76, N 11.43. Found: C 52.25, H 5.80, N 11.25.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 200 mg ofN-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]isoxazol-5-ylcarboxamidein CH₂Cl₂ (5 mL) was added dropwise to 0.07 mL DAST in CH₂CL₂ (10 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 321 mg as an oil. Thismaterial was purified via silica gel chromatography employing theChromatotron, using a 2000 micron rotor and eluting with a solvent ofhexane/ethyl acetate 1:1 to yield the final title compound (187 mg, 94%)as a semi-solid. Ion spray M.S. 368.2 (M*−1).

Calculated for: C₁₆H₂₀N₃O₄SF:

Theory: C 52.02, H 5.46, N 11.37. Found: C 51.70, H 5.59, N 10.88.

EXAMPLE 30 Preparation of4-(Dimethylamino)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]butanamide

Preparation of4-(Dimethylamino)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]butanamide

Into a 50 mL single-neck flask, 1 mL of oxalyl chloride was addedsyringe wise to 306 mg of 4-(dimethylamino)butyric acid hydrochloride inCH₂Cl₂ (20 mL) while stirring under a nitrogen atmosphere at roomtemperature. Then at this temperature. 1 drop of DMF was added bypipette and the mixture began to foam. The reaction was allowed to stirat this temperature for 1 h and was then concentrated under reducedvacuum to yield a yellow solid. This solid was added portion wise to a100 mL single-neck flask containing 460 mg of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine(prepared in example 19) and 183 mg of triethylamine in THF (25 mL)while stirring at room temperature under a nitrogen atmosphere. After 2h at this temperature, the mixture was concentrated under reduced vacuumand the resulting solid was taken into ethyl acetate. The organic layerwas backwashed once with H₂O, dried over K₂CO₃, and concentrated underreduced vacuum to yield 794 mg as an oil. This material was purified viasilica gel chromatography employing the Chromatotron while using a 4000micron rotor and eluting with an isocratic solvent of methanol/1% NH₄OHto yield intermediate title compound (350 mg, 51%) as a viscous oil. Ionspray M.S. 385 (M*).

Preparation of Final Title Compound

Scheme I, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 335 mg of4-(dimethylamino)-N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]butanamidein CH₂Cl₂ (5 mL) was added dropwise to 0.11 mL DAST in CH₂CL₂ (10 mL)while stirring at −78° C. under a nitrogen atmosphere. Reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 160 mg as an oil. Thismaterial was purified via silica gel chromatography employing theChromatotron, using a 2000 micron rotor and eluting with a solvent ofmethanol/1% NH₄OH to yield the final title compound (100 mg, 30%) as asemi-solid. Ion spray M.S. 388.0 (M*+1).

EXAMPLE 31 Preparation ofN-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-3-thienylcarboxamide

Preparation ofN-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-3-thienylcarboxamide

Scheme XII, Step A:[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine (300 mg,1.1 mmol, prepared in example 19), 3-thiophenecarboxylic acid (169 mg,1.2 mmol), triethylamine (333 mg, 3.0 mmol), 4-dimethylaminopyridine (15mg, DMAP), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-HCl (260 mg,1.2 mmol) and methylene chloride (25 mL) were mixed together in a 50 mLsingle neck flask and stirred under a nitrogen atmosphere at roomtemperature for 64 hours. The solution was then poured into H₂O, and thedesired product was extracted with ethyl acetate. The organic layer wasbackwashed once with H₂O, dried over K₂CO₃, and concentrated underreduced vacuum to yield 634 mg as an oil. This material was purified viasilica gel chromatography employing the Chromatotron, using a 4000micron rotor and eluting with a solvent of hexane/ethyl acetate 1:1 toyield intermediate title compound (151 mg, 36%) as a white solid. Ionspray M.S. 381.1 (M*+1).

Calculated for: C₁₇H₂₂N₂O₄S₂:

Theory: C 53.38, H 5.80, N 7.32. Found: C 53.29, H 5.79, N 7.39.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 100 mg ofN-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-3-thienylcarboxamidein CH₂Cl₂ (5 mL) was added dropwise to 0.03 mL DAST in CH₂CL₂ (5 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 111 mg as a foam. Thismaterial was triturated in hexane/ethyl acetate 19:1 for ½ h and thenfiltered to yield the final title compound (80 mg, 70%) as a whitesolid. Ion spray M.S. 385.1 (M*+1).

Calculated for: C₁₇H₂₁N₂O₃S₂F:

Theory: C 53.11, H 5.51, N 7.29. Found: C 52.93, H 5.44, N 7.15.

EXAMPLE 32 Preparation of{2-Fluoro-2-[4-(phenylmethoxy)phenyl]propyl}[(methylethyl)sulfonyl]amine

Preparation of 1-Amino-2-[4-(phenylmethoxy)phenyl]propan-2-ol

Into a 100 mL single-neck flask, 50 mL of trimethylsilyl cyanide wasadded dropwise to 26 g of 4′-benzyloxacetophenone and 3.9 g of zinciodide while stirring under a nitrogen atmosphere at room temperature.The reaction was allowed to stir at this temperature overnight. In themorning, the mixture was diluted with methylene chloride (100 mL) andthe organic layer was backwashed once with sat. Na₂HCO₃, dried overMgSO₄, and concentrated under reduced vacuum to yield 23.25 g. as anorange oil. Because of possible stability problems, this material wasused immediately and placed into 300 mL THF in a 1000 mL single-neckflask. While stirring at room temperature under a nitrogen atmosphere,100 mL of BH₃-THF complex was added syringe wise and the reaction wasstirred overnight. In the morning, 10 mL of con. hydrochloric acid wasadded dropwise at room temperature and severe foaming was present. Themixture was then concentrated under reduced vacuum. The resulting HClsalt was liberated while being stirred in 1N NaOH and the free amine wasextracted into ethyl acetate. This organic layer was washed with H₂O,dried over Na₂SO₄, and concentrated under reduced vacuum to yield 24.31g. as a semi-solid. This material was purified via silica gelchromatography employing the Water's prep. 2000 and eluting with agradient solvent of methylene chloride/methanol 9:1 to methanol/1% NH₄OHto yield intermediate title compound (8.61 g, 27%) as a white solid.(FD) M.S. 256.9 (M*).

Calculated for: C₁₆H₁₉NO₂:

Theory: C 74.68, H 7.44, N 5.44. Found: C 74.20, H 7.29, N 5.44.

Preparation of{2-Hydroxy-2-[4-(phenylmethoxy)phenyl]propyl}[(methylethyl)sulfonyl]amine

Scheme I, Step A: In a 1000 mL-3n flask fitted with a stirrer andthermometer, 5.69 g. of propanesulfonyl chloride was added dropwise to8.60 g. of 1-amino-2-[4-(phenylmethoxy)phenyl]propan-2-ol and 6.21 g. ofDBU in THF (300 mL) while stirring at 0° C. under a nitrogen atmosphere.The reaction was allowed to warm to room temperature and stirredovernight at this temperature. In the morning, reaction was concentratedunder reduced vacuum. The resulting oil was taken into ethyl acetate andthe organic layer was washed two times with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 10.2 g. as a solid. Thismaterial was purified via silica gel chromatography employing theWater's prep. 2000 and eluting with a solvent of hexane/ethyl acetate9:1 to yield intermediate title compound (6.14 g, 50%) as a white solid.Ion spray M.S. 362.2 (M*−1).

Calculated for: C₁₉H₂₅NO₄ S:

Theory: C 62.79, H 6.93, N 3.85. Found: C 62.85, H 6.89, N 3.88.

Preparation of Final Title Compound

Scheme I, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 400 mg of{2-hydroxy-2-[4-(phenylmethoxy)phenyl]propyl}[(methylethyl)sulfonyl]aminein CH₂Cl₂ (5 mL) was added dropwise to 0.1 mL DAST in CH₂CL₂ (5 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 340 mg as a yellow oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor while eluting with a solventof hexane/ethyl acetate 7:3 to yield the final title compound (271 mg,68%) as a semi-solid. Ion spray M.S. 364.2 (M*−1).

Calculated for C₁₉H₂₄NO₃SF:

Theory: C 62.44, H 6.62, N 3.83. Found: C 62.39, H 6.58, N 3.92.

EXAMPLE 33 Preparation of2-{[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenoxy]methyl}benzenecarbonitrile

Preparation of[2-Hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine

3.00 g of{2-hydroxy-2-[4-(phenylmethoxy)phenyl]propyl}[(methylethyl)sulfonyl]amine(prepared in example 32) and 3.10 g. of 10% Pd/C in ethyl acetate (300mL) were subjected to a hydrogen atmosphere while shaking at 60 psi'sfor 4 hours. Solution was filtered through a Celite mat and theresulting filtrate was concentrated under reduced vacuum to yieldintermediate title compound (2.48 g, 100%) as a foam. This materialslowly crystallized and was used without further purification. Ion sprayM.S. 272.1 (M*−1).

Calculated for C₁₂H₁₉NO₄S—½H₂O:

Theory: C 51.03, H 7.14, N 4.96 Found: C 51.20, H 7.21, N 4.71

Preparation of2-{[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenoxy]methyl}benzenecarbonitrile

Scheme XI, Step A: Into a 250 mL-3 neck flask fitted with a stirrer andthermometer, 400 mg of[2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF(10 mL) was added dropwise to 40 mg of NaH in DMF (30 mL) while stirringat room temperature under a nitrogen atmosphere. After stirring at thistemperature for 30 minutes, 290 mg of alpha-bromo 2-cyanotoluene in DMF(10 mL) was added dropwise followed by the addition of 184 mg of NaIportion wise. The reaction was then heated at 100° C. for 2 hours. Themixture was cooled to room temperature and poured into H₂O and thedesired product was extracted with ethyl acetate. This organic layer waswashed with H₂O, dried over K₂CO₃, and concentrated under reduced vacuumto yield 612 mg of a brown oil. This material was purified via silicagel chromatography employing the Chromatotron and using a 4000 micronrotor while eluting with a solvent of hexane/ethyl acetate 1:1 to yieldintermediate title compound (161 mg, 28%) as a viscous oil. Ion sprayM.S. 387.9 (M*−1).

Calculated for C₂₀H₂₄N₂O₄S:

Theory: C 61.84, H 6.23, N 7.21 Found: C 59.83, H 5.65, N 7.36

Preparation of Final Title Compound

Scheme XI, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 150 mg of2-{[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenoxy]methyl}benzenecarbonitrilein CH₂Cl₂ (5 mL) was added dropwise to 0.06 mL DAST in CH₂CL₂ (5 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 157 mg as a yellow oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor while eluting with a solventof hexane/ethyl acetate 9:1 to yield the final title compound (91 mg,60%) as a solid. Ion spray M.S. 389.2 (M*−1).

Calculated for C₂₀H₂₃N₂O₃SF:

Theory: C 61.52, H 5.94, N 7.17. Found: C 61.16, H 5.93, N 7.14.

EXAMPLE 34 Preparation of[2-Fluoro-2-(4-methoxyphenyl)propyl][(methylethyl)sulfonyl]amine

Preparation of 1-Amino-2-(4-methoxyphenyl)propan-2-ol

Into a 100 mL single-neck flask, 28.5 mL of trimethylsilyl cyanide wasadded dropwise to 10 g of 4′-methoxyacetophenone and 2.28 g of zinciodide while stirring under a nitrogen atmosphere at room temperature.The reaction was allowed to stir at this temperature overnight. In themorning, the mixture was diluted with methylene chloride (100 mL) andthe organic layer was backwashed once with sat. Na₂HCO₃, dried overMgSO₄, and concentrated under reduced vacuum to yield 13 g. as a tanoil. Because of possible stability problems, this material was usedimmediately and placed into 200 mL THF in a 500 mL single-neck flask.While stirring at room temperature under a nitrogen atmosphere, 70 mL ofBH₃-THF complex was added syringe wise and the reaction was stirredovernight. In the morning, 10 mL of concentrated hydrochloric acid wasadded dropwise at room temperature and severe foaming was present. Themixture was then concentrated under reduced vacuum. The resulting HClsalt was liberated while being stirred in 1N NaOH and the free amine wasextracted into ethyl acetate. This organic layer was washed with H₂O,dried over Na₂SO₄, and concentrated under reduced vacuum to yield 7.31g. of a 2 spot material. This material was purified via silica gelchromatography employing the Water's prep. 2000 and eluting with asolvent of methylene chloride/methanol 9:1 to yield intermediate titlecompound (3.01 g, 24%) as an oil as the top spot. (FD) M.S. 180.3(M*−1).

Calculated for: C₁₀H₁₅NO₂

Theory: C 66.27, H 8.34, N 7.73. Found: C 64.46, H 7.94, N 7.50.

Preparation of[2-Hydroxy-2-(4-methoxyphenyl)propyl][(methylethyl)sulfonyl]amine

Scheme I, Step A: In a 500 mL-3n flask fitted with a stirrer andthermometer, 2.53 g. of propanesulfonyl chloride was added dropwise to3.00 g. of 1-amino-2-(4-methoxyphenyl)propan-2-ol and 2.70 g. of DBU inTHF (200 mL) while stirring at 0° C. under a nitrogen atmosphere. Thereaction was allowed to warm to room temperature and stirred overnightat this temperature. In the morning, reaction was concentrated underreduced vacuum. The resulting oil was taken into ethyl acetate and theorganic layer was washed two times with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 3.61 g. as a solid. Thismaterial was purified via silica gel chromatography employing theWater's prep. 2000 and eluting with a solvent of hexane/ethyl acetate9:1 to yield intermediate title compound (2.71 g, 57%) as a white solid.Ion spray M.S. 286.2 (M*−1).

Preparation of Final Title Compound

Scheme I, Step B: Into a 50 mL 3 neck flask fitted with a stirrer andthermometer, 1.00 gm. of[2-hydroxy-2-(4-methoxyphenyl)propyl][(methylethyl)sulfonyl]amine inCH₂Cl₂ (5 mL) was added dropwise to 0.41 mL DAST in CH₂CL₂ (10 mL) whilestirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 1.07 g. as a yellow oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 4000 micron rotor while eluting with a solventof hexane/ethyl acetate 7:3 to yield the final title compound (851 mg,85%) as a viscous oil. Ion spray M.S. 288.1 (M*−1).

Calculated for C₁₃H₂₀NO₃SF:

Theory: C 53.96, H 6.97, N 4.84. Found: C 53.16, H 6.76, N 4.81.

EXAMPLE 35 Preparation of{2-[4-(3,5-Difluorophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine

Preparation of

Into a 500 mL single-neck flask fitted with a stirrer and thermometer,10.0 g. of 4′-iodoacetophenone, 1.0 g. of PdCl₂(dppf), and 17 mLtriethylamine were placed in Dioxane (160 mL) and stirred at roomtemperature under a nitrogen atmosphere. This solution was then degassedwith nitrogen for 15 minutes, followed by the addition of 8.8 mL pinacolborane syringe wise. Addition was exothermic and the solution turneddark immediately. The reaction was then heated at 85° C. for 6 h. Themixture was then cooled to room temperature and poured into H₂O and thedesired product was extracted with ether. This organic layer was washedwith H₂O, dried over MgSO₄, and concentrated under reduced vacuum toyield a white solid. This material was purified via silica gelchromatography employing the Water's prep. 2000 and eluting withhexane/ethyl acetate 19:1 to yield intermediate title compound,acetophenone derivative, (6.4 g, 64%) as a white powder.

Preparation of

Into a 25 mL single-neck flask, 1.6 mL of trimethylsilyl cyanide wasadded dropwise to 1.0 g. of the acetophenone derivative prepareddirectly above and 131 mg of zinc iodide while stirring under a nitrogenatmosphere at room temperature. The reaction was then stirred overnightat this temperature. In the morning the mixture was diluted withmethylene chloride (25 mL) and the organic layer was backwashed oncewith sat. Na₂HCO₃, dried over MgSO₄, and concentrated under reducedvacuum to yield 910 mg as a semi-solid. Because of possible stabilityproblems, this material was used immediately and placed into 20 mL THFin a 100 mL single-neck flask. While stirring at room temperature undera nitrogen atmosphere, 4 mL of BH₃-DMS complex was added syringe wiseand the reaction was refluxed for 4 hours. The reaction was cooled toroom temperature and 2 mL of con. hydrochloric acid was added dropwiseat room temperature and severe foaming was present. The mixture wasdiluted with ether (50 mL) and the reaction was stirred for anadditional hour. The precipitate that formed was collected by filtrationto yield intermediate title compound, amine derivative, (910 mg, 72%) asa white powder as the HCl salt.

Preparation of

In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 1.05 g.of propanesulfonyl chloride was added dropwise to 2.10 g. of the aminederivative prepared directly above, and 2.14 g. of DBU in THF (60 mL)while stirring at 0° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and stirred overnight at thistemperature. In the morning, reaction was concentrated under reducedvacuum. The resulting oil was taken into ethyl acetate and the organiclayer was washed two times with H₂O, dried over Na₂SO₄, and concentratedunder reduced vacuum to yield 600 mg as an oil. This material waspurified via silica gel chromatography employing the Chromatotron andusing a 4000 micron rotor while eluting with a solvent of hexane/ethylacetate 3:2 to yield intermediate title compound, sulfonyl derivative,(250 mg, 10%) as an oil. Ion spray M.S. 382.2 (M*−1).

Preparation of{2-[4-(3,5-difluorophenyl)phenyl]-2-hydroxypropyl}[(methylethyl)sulfonyl]amine

The sulfonyl derivative prepared directly above (250 mg, 0.65 mmol),1-bromo-3,5-difluorobenzene (138 mg, 0.71 mmol), sodium carbonate (1.1mL of a 2.0 M solution, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.65 mmol), and dioxane (10 mL) weremixed together in a 50 mL single neck flask and stirred at 70° C. overnight. In the morning, the reaction was cooled to room temperature andpoured into H₂O and the desired product was extracted with ethylacetate. The organic layer was backwashed once with H₂O, dried overK₂CO₃, and concentrated under reduced pressure to yield 286 mg of aviscous oil. This two spot material was purified via silica gelchromatography employing the Chromatotron and using a 2000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 1:1 to yieldintermediate title compound (73 mg, 31%, top spot) as a clear oil. Ionspray M.S. 368.2 (M*−1).

Preparation of Final Title Compound

Scheme I, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 22 mg of{2-[4-(3,5-difluorophenyl)phenyl]-2-hydroxypropyl}[(methylethyl)sulfonyl]aminein CH₂Cl₂ (2 mL) was added dropwise to 0.01 mL DAST in CH₂CL₂ (3 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield 18.4 mg as a yellow oil. Thismaterial was purified via silica gel chromatography employing theChromatotron and using a 1000 micron rotor while eluting with a solventof hexane/ethyl acetate 7:3 to yield the final title compound (12 mg,52%) as a viscous oil. Ion spray M.S. 370.2 (M*−1).

EXAMPLE 36 Preparation of[(Dimethylamino)sulfonyl][2-fluoro-2-(4-iodophenyl)propyl]amine

Preparation of[(Dimethylamino)sulfonyl][2-hydroxy-2-(4-iodophenyl)propyl]amine

Scheme X, Step A: In a 500 mL-3 neck flask fitted with a stirrer andthermometer, 358 mg of dimethylsulfamoyl chloride was added dropwise to554 mg of 1-amino-2-(4-iodophenyl)propan-2-ol (intermediate prepared inexample 1) and 380 mg of DBU in THF (125 mL) while stirring at 0° C.under a nitrogen atmosphere. The reaction was allowed to warm to roomtemperature and stirred overnight at this temperature. In the morning,reaction was concentrated under reduced vacuum. The resulting oil wastaken into ethyl acetate and the organic layer was washed two times withH₂O, dried over Na₂SO₄, and concentrated under reduced vacuum to yieldan oil. This material was purified via silica gel chromatographyemploying the Chromatotron and using a 2000 micron rotor while elutingwith a solvent of hexane/ethyl acetate 3:1 to yield intermediate titlecompound (257 mg, 33%) as a white solid. (Fd) M.S. 384 (M*).

Calculated for: C₁₁H₁₇N₂O₃SI:

Theory: C 34.39, H 4.46, N 7.29. Found: C 33.25, H 4.24, N 6.80.

Preparation of Final Title Compound

Scheme X, Step B: Into a 50 mL 3 neck flask fitted with a stirrer andthermometer, 257 mg of[(dimethylamino)sulfonyl][2-hydroxy-2-(4-iodophenyl)propyl]amine inCH₂Cl₂ (10 mL) was added dropwise to 0.08 mL DAST in CH₂CL₂ (10 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield a yellow oil. This materialwas purified via silica gel chromatography employing the Chromatotronand using a 2000 micron rotor while eluting with a solvent ofhexane/ethyl acetate 3:1 to yield the final title compound (147 mg, 57%)as a white solid; m.p. 115°–117° C. Ion spray M.S. 385 (M*+1).

Calculated for: C₁₁H₁₆N₂O₂SI:

Theory: C 34.21, H 4.18, N 7.25. Found: C 34.04, H 4.41, N 7.59.

EXAMPLE 37 Preparation of4-[4-(2-{[(Dimethylamino)sulfonyl]amino}-1-fluoroisopropyl)phenyl]benzenecarbonitrile

Preparation of4-[4-(2-{[(Dimethylamino)sulfonyl]amino}-1-hydroxyisopropyl)phenyl]benzenecarbonitrile

Scheme VI, Step A:[(Dimethylamino)sulfonyl][2-hydroxy-2-(4-iodophenyl)propyl]amine (384mg, 1.0 mmol, prepared in example 36), 4-cyanobenzene boronic acid (191mg, 1.3 mmol), potassium carbonate (179 mg, 1.3 mmol),tetrakis(triphenyl phosphine)palladium(0) (58 mg, 0.05 mmol), anddioxane/water (60 mL, 3:1) were mixed together in a 100 mL single neckflask and stirred at 70° C. over night. In the morning, the reaction wascooled to room temperature and poured into H₂O and the desired productwas extracted with ethyl acetate. The organic layer was backwashed oncewith H₂O, dried over K₂CO₃, and concentrated under reduced pressure toyield a viscous oil. This two spot material was purified via silica gelchromatography employing the Chromatotron and using a 2000 micron rotorwhile eluting with a solvent of methylene chloride/ethyl acetate 9:1 toyield intermediate title compound (255 mg, 71%, bottom spot) as a whitesolid. (FD) M.S. 359 (M*).

Calculated for: C₁₈H₂₁N₃O₃S—¼H₂O:

Theory: C 59.34, H 5.77, N 11.54. Found: C 58.89, H 5.63, N 11.26.

Preparation of Final Title Compound

Scheme VI, Step B: Into a 25 mL 3 neck flask fitted with a stirrer andthermometer, 209 mg of4-[4-(2-{[(dimethylamino)sulfonyl]amino}-1-hydroxyisopropyl)phenyl]benzenecarbonitrilein CH₂Cl₂ (2 ml) was added dropwise to 0.07 mL DAST in CH₂CL₂ (3 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer was washed with H₂O, dried over Na₂SO₄, andconcentrated under reduced vacuum to yield a solid. This material waspurified via silica gel chromatography employing the Chromatotron andusing a 2000 micron rotor while eluting with a solvent of hexane/ethylacetate 3:1 to yield the final title compound (132 mg, 63%) as a whitesolid. (FD) M.S. 361 (M*).

EXAMPLE 38 Preparation of{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine

[(Dimethylamino)sulfonyl][2-fluoro-2-(4-iodophenyl)propyl]amine (386,1.0 mmol, prepared in example 36), 3-aminobenzeneboronic acid (201 mg,1.3 mmol), potassium carbonate (179 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), and dioxane/water (60 mL,3:1) are mixed together in a 100 mL single neck flask and stirred at 70°C. over night. In the morning, the reaction is cooled to roomtemperature and poured into H₂O, and the desired product is extractedwith ethyl acetate. The organic layer is backwashed once with H₂O, driedover K₂CO₃, filtered, and concentrated under reduced pressure. The crudematerial is purified via silica gel chromatography employing theChromatotron and using a 2000 micron rotor with hexane/ethyl acetateeluent to provide the title compound.

EXAMPLE 39 Preparation of[(Dimethylamino)sulfonyl][2-fluoro-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl]amine

In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 285 mgof methanesulfonyl chloride is added dropwise to 350 mg of{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine(prepared in example 38) and 380 mg of DBU in THF (125 mL) whilestirring at 0° C. under a nitrogen atmosphere. The reaction is allowedto warm to room temperature and then stirred overnight at thistemperature. In the morning, the reaction is concentrated under reducedvacuum. The resulting material is taken into ethyl acetate and theorganic layer is washed two times with H₂O, dried over Na₂SO₄, filtered,and concentrated under reduced vacuum. This crude material is purifiedvia silica gel chromatography employing the Chromatotron and using a4000 micron rotor with hexane/ethyl acetate eluent to provide the titlecompound.

EXAMPLE 40 Preparation of[(Dimethylamino)sulfonyl]{2-fluoro-2-[4-(3-{[(methylethyl)sulfonyl]amino}phenyl)phenyl]propyl}amine

In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 356 mgof 2-propanesulfonyl chloride is added dropwise to 350 mg of{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine(prepared in example 38) and 380 mg of DBU in THF (125 mL) whilestirring at 0° C. under a nitrogen atmosphere. The reaction is allowedto warm to room temperature and then stirred overnight at thistemperature. In the morning, the reaction is concentrated under reducedvacuum. The resulting material is taken into ethyl acetate and theorganic layer is washed two times with H₂O, dried over Na₂SO₄, filtered,and concentrated under reduced vacuum. This crude material is purifiedvia silica gel chromatography employing the Chromatotron and using a4000 micron rotor with hexane/ethyl acetate eluent to provide the titlecompound.

EXAMPLE 41 Preparation of4-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenesulfonamide

Preparation of 4-Bromobenzenesulfonamide

4-Bromobenzenesulfonyl chloride (1.0 g, 3.9 mmol), methanol/ammoniasolution (5 mL, excess), and methanol (5 mL) were mixed together in a 25mL-single neck flask and stirred overnight under a nitrogen atmosphere.In the morning, the reaction was concentrated under reduced vacuum toyield intermediate title compound (1.13 g, 100%) as a white solid. Thismaterial was used without further purification. Ion spray M.S. 235.9(M*).

Preparation of4-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzensulfonamide

4-bromobenzenesulfonamide (236 mg, 1.0 mmol), the intermediate sulfonylderivative prepared in example 35 of structure:

(575 mg, 1.5 mmol), sodium carbonate (1.2 mL of a 2.0 M solution, 1.5mmol), tetrakis(triphenyl phosphine)palladium(0) (50 mg, 0.65 mmol), anddioxane (20 mL) are mixed together in a 50 mL single neck flask andstirred at 70° C. over night. In the morning, the reaction is cooled toroom temperature and poured into H₂O and the desired product isextracted with ethyl acetate. The organic layer is backwashed once withH₂O, dried over K₂CO₃, filtered, and concentrated under reducedpressure. This crude material is purified via silica gel chromatographyemploying the Chromatotron and using a 4000 micron rotor to provide thetitle compound.

Preparation of Final Title Compound

Scheme I, Step B: Into a 50 mL 3 neck flask fitted with a stirrer andthermometer, 412 mg of4-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenesulfonamidein CH₂Cl₂ (10 mL) is added dropwise to 0.14 mL DAST in CH₂CL₂ (10 mL)while stirring at −78° C. under a nitrogen atmosphere. The reaction isallowed to warm to room temperature and diluted with CH₂Cl₂ (25 mL).This organic layer is washed with H₂O, dried over Na₂SO₄, filtered, andconcentrated under reduced vacuum. This crude material is purified viasilica gel chromatography employing the Chromatotron and using a 4000micron rotor with hexane/ethyl acetate eluent to provide the titlecompound.

EXAMPLE 42 Preparation ofN-(2-{3-Fluoro-4′-[1-fluoro-1-methyl-2-(propane-2Sulfonylamino)ethyl]-biphenyl-4-yl}-ethyl)-isobutyramide

Preparation of (4-Bromo-2-fluoro-phenyl)-acetonitrile

Sodium cyanide (1.37 g, 28.00 mmol) was added to a stirred solution of2-fluoro-4-bromo benzyl bromide (5.0 g, 18.66 mmol) in dry DMSO (60 mL)at ambient temperature under nitrogen. The reaction was stirred for 4 hat ambient temperature then poured into H₂O (150 mL) and extracted withEtOAc. The organic layer was washed with brine, dried (MgSO₄), filtered,and concentrated in vacuo to give the intermediate title compound as abrown oil (3.85 g, 96%). Electrospray mass spectrum: M=213, M+2=215

Preparation of1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2yl)phenylethanone

4-Iodo acetophenone (10.00 g, 40.64 mmol), PdCl₂(dppf).CH₂Cl₂ (1.00 g,1.22 mmol) dry dioxane (160 mL) and Et₃N (17.0 mL, 121.96 mmol) werecombined in a dry flask which had been purged with N₂ several times.Pinacol borane (8.80 mL, 60.96 mmol) was added and the reaction mixturewas heated at reflux for 4 h then cooled to ambient temperature, pouredinto Diethyl ether (250 mL) and extracted with H₂O and washed withbrine. The Diethyl ether was dried (MgSO₄), filtered and the filtrateconcentrated in vacuo. Purification by gradient chromatography on silica(hexane, 5% EtOAc/hexane) followed by recrystallization (hexane) gave6.4 g (64%) of the intermediate title compound as a white powder.

Preparation of2-[4(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-trimethylsilanyloxy-propionitrile

Scheme Va, Step A: 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2yl)phenyl-ethanone (1.0 g, 4.06 mmol) dissolved in THF(1.0 mL) was added to ZnI₂ (0.131 g, 0.41 mmol). To this stirred mixtureunder N₂ was added dropwise TMSCN (1.6 mL, 12.18 mmol) and the reactionmixture was stirred at ambient temperature overnight. The resultingmixture was extracted with NaHCO₃, H₂O, washed with brine, dried(MgSO₄), filtered, and concentrated in vacuo to give the intermediatetitle compound as a yellow oil 0.91 g (65%).

Preparation of1-Amino-2-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-olHydrochloride

Scheme Va, Step B: Borane dimethyl sulfide 2.0 M (4.0 mL, 8.0 mmol) wasadded dropwise to2-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-2-trimethylsilanyloxy-propionitrile(0.910 g, 2.64 mmol) in dry THF (20.0 mL) at ambient temperature. Afterthe initial exotherm, the reaction mixture was heated and stirred atreflux for 4 h cooled to ambient temperature and quenched by a slowaddition of concentrated HCl. The reaction was diluted with Diethylether and stirred for approximately 1 h. The resulting white precipitatewas collected by filtration and used in the next reaction.

Preparation ofN-{2-Hydroxy-2-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)phenyl]propyl}-2-propanesulfonamide

Isopropyl sulfonamide (0.313 g, 2.2 mmol) is added to1-Amino-2-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-olhydrochloride (0.627 g, 2.0 mmol) in CH₂Cl₂ (20 mL) at 0° C.Triethylamine (0.505 g, 5.0 mmol) is then added and the resultingmixture is stirred for 4 h at 0° C. The reaction mixture is extractedwith H₂O, washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue is purified by chromatography onsilica gel with EtOAc/hexane to provide the intermediate title compound.

Preparation ofN-[2-(4′-Cyanomethyl-3′-fluoro-biphenyl-4yl)-2-hydroxy-propyl]-2-propanesulfonamide

(4-Bromo-2-fluoro-phenyl)-acetonitrile (0.255 g, 1.19 mmol),PdCl₂(dppf).CH₂Cl₂ (0.039 g, 0.048 mmol) andN-{2-hydroxy-2-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)phenyl]propyl}-2-propanesulfonamide(0.383 g, 1.0 mmol) are mixed together in dry DMF (30 mL) under N₂ atambient temperature. To this stirred mixture is added 2M Na₂CO₃ (1.25mL, 2.5 mmol) and the resulting mixture is heated and stirred at 80° C.for 6 h. The mixture is cooled and poured into EtOAc. The EtOAc isextracted several times with H₂O, washed with brine, dried (MgSO₄),filtered, and the filtrate evaporated in vacuo. Chromatography on silicagel eluting with EtOAc/hexane gives the intermediate title compound.

Preparation of N-2-[4-(4′-AminoEthyl-3′-fluorophenyl)phenyl]2-hydroxy-propyl-2-propanesulfonamide

Borane dimethyl sulfide (3.0 mL, 6.0 mmol) is added toN-[2-(4′-cyanomethyl-3′-fluoro-biphenyl-4yl)-2-hydroxy-propyl]-2-propanesulfonamide(0.78 g, 2.0 mmol) in THF (20 mL) and the resulting solution is heatedand stirred at reflux for 4 h. The resulting mixture is cooled andacidified cautiously with concentrated HCl. Collection of theprecipitated solid by filtration yields the intermediate title compound.

Preparation ofN-(2-{3-Fluoro-4′-[1-hydroxy-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4yl}-ethyl)-isobutyramide

To N-2-[4-(4′-aminoethyl-3′-fluorophenyl)phenyl]2-hydroxy-propyl-2-propanesulfonamide(0.104 g, 0.26 mmol) in dry CH₂Cl₂ in a 12 mL vial is added Et₃N (81 μL,0.50 mmol), and isobutyryl chloride (34 μL, 0.32 mmol) respectively. Thereaction vial is stirred overnight at ambient temperature. The resultingmixture is diluted with CH₂Cl₂ washed successively with 1M HCl,saturated NaHCO₃, brine, dried (MgSO₄), filtered, and concentrated togive the intermediate title compound.

Preparation of Final Title Compound

Scheme I, Step B: To DAST (26 μL, 0.20 mmol) in CH₂Cl₂(0.3 mL) under N₂at −78° C. is added dropwiseN-(2-{3-fluoro-4′-[1-hydroxy-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4yl}-ethyl)-isobutyramide(0.0928 g, 0.20 mmol) in CH₂Cl₂ (1.0 mL). Following addition the dry iceacetone-cooling bath is replaced with an ice water bath and the reactionmixture allowed to warm to ambient temperature. The reaction mixture isdiluted with CH₂Cl₂, extracted with H₂O, dried (Na₂SO₄), filtered, andthe filtrate is evaporated to dryness to give the title compound.

EXAMPLE 43 Preparation ofN-(2-{3-Fluoro-4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)ethyl]-biphenyl-4-yl}-ethyl)-acetamide

Preparation ofN-(2-{3-Fluoro-4′-[1-hydroxy-1-methyl-2-(propane-2-sulfonylamino)ethyl]-biphenyl-4yl}-ethyl)-acetamide

To N-2-[4-(4′-Aminoethyl-3′-fluorophenyl)phenyl]2-hydroxy-propyl-2-propanesulfonamide(0.104 g, 0.26 mmol, intermediate prepared in example 42), in dry CH₂Cl₂in a 12 mL vial is added Et₃N (81 μL, 0.50 mmol) and acetyl chloride (23μL, 0.32 mmol) respectively. The reaction vial is stirred overnight atambient temperature. The resulting mixture is diluted with CH₂Cl₂,washed successively with 1M HCl, saturated NaHCO₃, brine, dried (MgSO₄),filtered, and concentrated to provide the intermediate title compound.

Preparation of Final Title Compound

Scheme I, Step B: To DAST (26 μL, 0.20 mmol) in CH₂Cl₂(0.3 mL) under N₂at −78° C is added dropwiseN-(2-{3-fluoro-4′-[1-hydroxy-1-methyl-2-(propane-2-sulfonylamino)ethyl]-biphenyl-4yl}-ethyl)-acetamide(0.087 g. 0.20 mmol) in CH₂Cl₂(1.0 mL). Following addition the dry iceacetone-cooling bath is replaced with an ice water bath and the reactionmixture allowed to warm to ambient temperature. The reaction mixture isdiluted with CH₂Cl₂, extracted with H₂O, dried (Na₂SO₄), filtered, andthe filtrate is evaporated to dryness to give the final title compound.

EXAMPLE 44 Preparation ofN-{2-(2-Fluoro-2-[3′-fluoro-4′-(2-methanesulfonylamino)-ethyl)-biphenyl-4-yl]propyl}-2-propaneSulfonamide

Preparation ofN-(2-{3′-Fluoro-4′-[2-methanesulfonylamino)-ethyl]-biphenyl}-2-hydroxy-propyl)-2-propanesulfonamide

N-2-[4-(4′-Aminoethyl-3′-fluorophenyl)phenyl]2-hydroxy-propyl-2-propanesulfonamide(0.104 g, 0.26 mmol, prepared in example 42), Et₃N (81 μL, 0.50 mmol)and methane sulfonyl chloride (23 μL, 0.30 mmol) are combined withmethylene chloride in a 12 mL vial. The reaction vial is stirredovernight at ambient temperature. The resulting mixture is diluted withCH₂Cl₂, washed successively with 1M HCl, saturated NaHCO₃, brine, dried(MgSO₄), filtered, and concentrated to provide the intermediate titlecompound.

Preparation of Final Title Compound

Scheme I, Step B: To a solution of DAST (26 μL, 0.20 mmol) in CH₂Cl₂(0.3 mL) under N₂ is added dropwiseN-(2-{3′-fluoro-4′-[2-methanesulfonylamino)ethyl]-biphenyl}-2-hydroxy-propyl)-2-propanesulfonamide(0.094 g, 0.20 mmol) in CH₂Cl₂ (1.0 mL) at −78° C. Following additionthe dry ice acetone-cooling bath is replaced with an ice water bath andthe reaction mixture allowed to warm to ambient temperature. Thereaction mixture is diluted with CH₂Cl₂, extracted with H₂O, dried(Na₂SO₄), filtered, and the filtrate is evaporated to dryness to givethe final title compound.

EXAMPLE 45 Preparation ofN-{2-(2-Fluoro-2-[3′-fluoro-4′-(2-(propane-2-sulfonylamino)-ethyl)-biphenyl-4-yl]propyl}-2-propaneSulfonamide

Preparation ofN-(2-{3′-Fluoro-4′-[2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-yl}-2-hydroxy-propyl)-2-propaneSulfonamide

N-2-[4-(4′-Aminoethyl-3′-fluorophenyl)phenyl]2-hydroxy-propyl-2-propanesulfonamide(0.104 g, 0.26 mmol, prepared in example 42), Et₃N (81 μL, 0.50 mmol)and isopropyl sulfonyl chloride (34 μL, 0.30 mmol) are combined withmethylene chloride in a 12 mL vial. The reaction vial is stirredovernight at ambient temperature. The resulting mixture is diluted withCH₂Cl₂, washed successively with 1M HCl, saturated NaHCO₃, brine, dried(MgSO₄), filtered, and concentrated to provide the intermediate titlecompound.

Preparation of Final Title Compound

Scheme I, Step B: To a solution of DAST (26 μL, 0.20 mmol) in CH₂Cl₂(0.3 mL) under N₂ is added dropwiseN-(2-{3′-fluoro-4′-[2-(propane-2-sulfonylamino)-ethyl]-biphenyl}-2-hydroxy-propyl)-2-propanesulfonamide(0.100 g, 0.20 mmol) in CH₂Cl₂ (1.0 mL) at −78° C. Following additionthe dry ice acetone-cooling bath is replaced with an ice water bath andthe reaction mixture allowed to warm to ambient temperature. Thereaction mixture is diluted with CH₂Cl₂, extracted with H₂O, dried(Na₂SO₄), filtered, and the filtrate is evaporated to dryness to givethe final title compound.

EXAMPLE 46 Preparation of N-{2-Fluoro-2-[4(2-oxo-2,3-dihydro-1H-indolo-5yl)-phenyl]-propyl}-2-propane sulfonamide

Preparation of 5-Bromo-oxindole

Oxindole (1.30 g, 0.010 mmol) was suspended in dry acetonitrile (22.0mL) under N₂ and cooled to −10° C. To this stirred mixture was addedrecrystallized NBS (2.00 g, 0.011 mol) portionwise. The resultingsuspension was stirred at −10 to 10° C. for 3 h. The precipitated solidwas collected by filtration, washed with H₂O and dried to give theintermediate title compound as an off white solid 1.75 g (82%).Electrospray mass spectrum (M−1)=210, (M−1)=211

Preparation of N-{2-Hydroxy-2-[4(2-oxo-2,3-dihydro-1H-indolo-5yl)-phenyl]-propyl}-2-propane sulfonamide

To a stirred mixture ofN-{2-hydroxy-2-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)phenyl]propyl}-2-propanesulfonamide(0.383 g, 1.0 mmol, intermediate prepared in example 42), PdCl₂(dppf).CH₂Cl₂ (0.033 g, 0.04 mmol) and 5-bromo-oxindole (0.276 g, 1.3 mmol) inDMF (20 mL) under N₂ is added 2M Na₂CO₃ (1.35 mL, 2.7 mmol) and thereaction mixture is heated and stirred under N₂ for 6 h. The reactionmixture is allowed to warm to ambient temperature and poured into EtOAc(100 mL). The organic layer is washed with H₂O and brine, dried (MgSO₄)filtered and the filtrate evaporated in vacuo. Chromatography on silicagel with EtOAc/hexane gives the intermediate title compound.

Preparation of Final Title Compound

Scheme I, Step B: To a stirred solution of DAST (26 μL, 0.20 mmol) in(0.3 mL) of CH₂Cl₂ under N₂ at −78° C. is addedN-{2-hydroxy-2-[4(2-oxo-2,3-dihydro-1H-indolo-5yl)-phenyl]-propyl}-2-propane sulfonamide (0.077 g, 0.20 mmol).Following addition the dry ice acetone-cooling bath is replaced with anice water bath and the reaction mixture allowed to warm to ambienttemperature. The reaction mixture is diluted with CH₂Cl₂, extracted withH₂O, dried (Na₂SO₄), filtered, and the filtrate is evaporated to drynessto provide the final title compound.

EXAMPLE 47 Preparation of{4′-[1-Fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-3-nitro-biphenyl-4-yl}-aceticAcid Ethyl Ester

Preparation of 2-(4-Bromo-2-nitro-phenyl)-malonic Acid Diethyl Ester

Diethyl malonate (3.34 mL, 22 mmol) was added cautiously to a stirredsuspension of 60% NaH (0.96 g, 24 mmol) in dry DMF (50 mL) at −10° C.under N₂. The resulting mixture was stirred at −10 to 10° C. for 1 h. Tothis mixture at 0° C. was added 2,4-dibromo-nitrobenzene (3.34 mL, 0.022mol) portionwise. The mixture was allowed to warm to ambient temperatureand stirred overnight. Evaluation by TLC (EtOAc-hexane 4:1) showed onlya trace of starting material. The reaction mixture was poured into a twophase Diethyl ether-1M HCl mixture. The yellow Diethyl ether layer wasdried (MgSO₄), filtered, and evaporated in vacuo. Chromatography onsilica gel, eluting with EtOAc-hexane 5:95 gave a yellow liquid whichrapidly solidified to give the intermediate title compound (2.50 g,69%), mp 54–55° C.

Preparation of (4-Bromo-2-nitro-phenyl)-acetic Acid Ethyl Ester

To a stirred solution of concentrated HCl (18.00 mL) diluted to 72.00 mLwith 95% Ethanol was added 2-(4-bromo-2-nitro-phenyl)-malonic aciddiethyl ester (2.50 g, 6.94 mmol). The resulting mixture was then heatedat reflux under N₂ for 4 h. The reaction mixture was allowed to cool toambient temperature and poured into H₂O (250 mL). This aqueous mixturewas then extracted with 2×150 mL of Diethyl ether. The Et₂O layer wasextracted with H₂O and 5% NaHCO₃ washed with brine, dried (MgSO₄), andfiltered. Evaporation of the filtrate in vacuo gave the intermediatetitle compound as a yellow liquid (1.52 g, 76%).

Preparation of{4′-[1-Hydroxy-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-3-nitro-biphenyl-4-yl}-aceticAcid Ethyl Ester

PdCl₂(dppf).CH₂Cl₂ (0.077 g, 0.90 mmol) andN-{2-hydroxy-2-[4(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)phenyl]propyl}-2-propanesulfonamide (0.383, 1.0 mmol,intermediate prepared in example 42) are mixed together in a dry flaskunder N₂ followed by (4-bromo-2-nitro-phenyl)-acetic acid ethyl ester(0.300 g, 1.04 mmol), CsCO₃ (0.68 g, 2.09 mmol) and toluene(65 mL)respectively. The resulting mixture is heated and stirred at 96° C. for5 h. The reaction mixture is allowed to cool to ambient temperature andis stirred overnight. The toluene is diluted with EtOAc (100 mL) andfiltered through celite. The resulting filtrate is extracted with 2×200mL of H₂O, washed with brine, dried (MgSO₄), and filtered. The filtrateis evaporated and chromatographed on silica gel, eluting withEtOAc-hexane to give the intermediate title compound.

Preparation of Final Title Compound

Scheme I, Step B: To a solution of DAST (118 μL, 0.998 mmol) in CH₂Cl₂(0.8 mL) under N₂ at −78° C. is added{4′-[1-hydroxy-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-3-nitro-biphenyl-4-yl}-aceticacid ethyl ester (0.465 g, 1.00 mmol) in CH₂Cl₂ (3.0 mL). Followingaddition the dry ice acetone-cooling bath is replaced with an ice waterbath and the reaction mixture allowed to warm to ambient temperature.The reaction mixture is diluted with CH₂Cl₂, extracted with H₂O, dried(Na₂SO₄), filtered, and the filtrate is evaporated to dryness to providethe final title compound.

EXAMPLE 48 Preparation of{4′-[1-Fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-3-nitrobiphenyl-4-yl}-aceticAcid

To a solution of{4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-3-nitro-biphenyl-4-yl}-aceticacid ethyl ester. (0.341 g, 0.731 mmol, prepared in example 47) inEthanol (5.0 mL) is added a solution of 6.7% NaOH (15.0 mL) and theresulting mixture is stirred under N₂ at ambient temperature for 72 h.The mixture is diluted with H₂O (100 mL) and acidified with 37% HCl.Extraction with EtOAc followed by drying (MgSO₄), filtration, andevaporation of the filtrate in vacuo gives the title compound.

EXAMPLE 49 Preparation ofN-{2-Fluoro-2-[4-(2-oxo-2,3-dihydro-1H-indol-6-yl)-phenyl]-propyl)-2-propanesulfonamide

To a stirred solution of{4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)ethyl]-3-nitro-biphenyl-4-yl}-aceticacid (0.311 g, 0.71 mmol, prepared in example 48) dissolved in Ethanol(4.0 mL)/50% H₂SO₄ (3.0 mL) at ambient temperature then heated to 90° C.is added Zn (0.186 g, 2.84 mmol) in divided portions over 30 minutes.Heating and stirring is continued for 2 h after addition of the Zn. Themixture is allowed to cool to ambient temperature. It is then extracted(EtOAc) and the EtOAc is extracted with 5% NaHCO₃, washed with brine,dried (MgSO₄), filtered and the filtrate concentrated in vacuo.Chromatography of the residue (silica gel, EtOAc/hexane) provides thetitle compound.

EXAMPLE 50 Preparation of Methyl6-{N-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylate

Preparation of Methyl6-{N-[4-(1-Hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylate

Scheme XII, Step A: Into a 50 mL single neck flask, 1 mL oxalyl chloridewas added syringe wise to 5-(methoxycarbonyl)-pyridine-2-carboxylic acid(271 mg, 1.5 mmol) in methylene chloride (10 mL) while stirring undernitrogen at room temperature. Immediately, 1 drop of DMF was added bypipette initiating a foaming of the mixture. The reaction was stirredone hour at this temperature and then concentrated under reduced vacuumto yield a white semi-solid. This material was placed into THF (5 mL)and added dropwise to a stirring solution of[2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine (400 mg,1.5 mmol, intermediate prepared in example 19) and triethlyamine (152mg) in THF (20 mL) at room temperature and the mixture was stirredovernight. In the morning, the solution was concentrated under reducedvacuum and the resulting oil was taken into methylene chloride and theorganic layer was washed once with H₂O, dried over K₂CO₃, filtered, andconcentrated under reduced vacuum to yield 244 mg as an orange solid.This material was purified via silica gel chromatography employing thechromatotron and using a 4000 micron rotor while eluting with a solventof ethyl acetate to yield the intermediate title compound (165 mg, 25%)as a yellow solid. Ion spray M.S. 434.2 (M*−1).

Calculated for C₂₀H₂₅N₃O₆S—H₂O:

Theory: C 52.95, H 6.00, N 9.27. Found: C 53.14, H 5.67, N 9.01.

Preparation of Final Title Compound

Scheme XII, Step B: Into a 50 mL, 3 necked flask fitted with a stirrerand thermometer, 200 mg of methyl6-{N-[4-(1-hydroxy-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylatein methylene chloride (5 mL) is added dropwise to 0.06 mL DAST inmethylene chloride (5 mL) while stirring at −78° C. under a nitrogenatmosphere. Reaction is allowed to warm to room temperature and dilutedwith methylene chloride (25 mL). This organic layer is washed with H₂O,dried over Na₂SO₄, filtered, and concentrated under reduced vacuum toyield a slowly crystallizing yellow oil (80% yield). This material wasused without further purification. Ion spray M.S. 436.3 (M*−1).

Calculated for C₂₀H₂₄N₃O₅SF:

Theory: C 54.91, H 5.53, N 9.60. Found: C 54.10, H 5.66, N 9.12.

EXAMPLE 51 Preparation of6-{N-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylicAcid

Methyl6-{N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylate(150 mg, 0.35 mmol, prepared in example 50), lithium hydroxide (52 mg,1.24 mmol), tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL)were mixed together in a 25 mL 3 neck flask and stirred over night atroom temperature. In the morning, the mixture was concentrated underreduced vacuum to yield a white solid. This material was taken into 1NHCl and the desired material was extracted into methylene chloride. Theacidic solution was taken to pH 10 with 1N NaOH and the resultingprecipitate was again extracted with methylene chloride. Both organiclayers were combined and washed once with H₂O, dried over MgSO₄,filtered, and concentrated under reduced vacuum to yield the titlecompound (125 mg, 84%) as a tan solid. This material was used withoutfurther purification. Ion spray M.S. 403.9 (M*−19 Fluorine).

EXAMPLE 52 Preparation ofN-[4-(1-Fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl][5-(N-methylcarbamoyl)(2-pyridyl)]carboxamide

Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringewise to6-{N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylicacid. (110 mg, 0.26 mmol, prepared in example 51) in methylene chloride(10 mL) while stirring under nitrogen at room temperature. Immediately,1 drop of DMF was added by pipette initiating a foaming of the mixture.The reaction was stirred one hour at this temperature and thenconcentrated under reduced vacuum to yield a white semi-solid. Thismaterial was placed into dioxane (10 mL) and added dropwise to astirring solution of 40% methylamine in water (3 mL, excess) at roomtemperature and the mixture was stirred overnight. In the morning, thesolution was concentrated under reduced vacuum and the resulting oil wastaken into methylene chloride and the organic layer was washed once withH₂O, dried over K₂CO₃, filtered, and concentrated under reduced vacuumto yield 78 mg as an oil. This material was purified via silica gelchromatography employing the chromatotron and using a 1000 micron rotorwhile eluting with a solvent of ethyl acetate to yield the titlecompound (28 mg, 25%) as a white solid. Ion spray M.S. 435.2 (M*−1) and417.1 (M*−19 Fluorine).

Calculated for C₂₀H₂₅N₄O₄SF:

Theory: C 55.03, H 5.77, N 12.83. Found: C 55.85, H 6.09, N 12.02.

EXAMPLE 53 Preparation of Propane-2-sulfonic Acid[2-Fluoro-2-(2-fluoro-4-methoxy-phenyl)propyl]-amide

Preparation of2-(2-Fluoro-4-methoxy-phenyl)-2-trimethylsilanyloxy-propionitrile

Scheme IV, Step A: 2′-Fluoro-4′-methoxy acetophenone (2.0 g, 11.89 mmol)was combined with zinc iodide (0.38 g, 1.19 mmol) in a 50 mL roundbottom flask. Trimethylsilyl cyanide (4.8 mL, 35.67 mmol) was slowlyadded dropwise to the solid mixture, with the generation of heat. Theresulting dark brown solution was stirred at room temperature undernitrogen overnight. The mixture was diluted with CHCl₃ and washed withNaHCO₃, water and brine, dried (MgSO₄), filtered, and concentrated to ayellow oil that was used in the next step without purification.

Preparation of 2-(2-Fluoro-4-methoxy-phenyl)-2-hydroxy-propylamineHydrochloride

Scheme IV, Step B:2-(2-Fluoro-4-methoxy-phenyl)-2-trimethylsilanyloxy-propionitrile (2.8g, 10.47 mmol) was dissolved in dry THF (30 mL) and stirred at roomtemperature under nitrogen. A 2.0 M solution of borane-dimethylsulfidecomplex (15.7 mL, 31.41 mmol) was added dropwise and the reaction washeated at reflux for 3 hours then cooled to room temperature.Concentrated HCl was carefully added dropwise until the evolution of gasceased. The reaction mixture was diluted with diethyl ether and a whiteprecipitate formed. The solids were collected and washed with additionalether to give 2.5 g (100%) of2-(2-fluoro-4-methoxy-phenyl)-2-hydroxy-propylamine hydrochloride.Electrospray mass spectrum (M−1)=199.99 (free amine)

Preparation of Propane-2-sulfonic Acid[2-(2-Fluoro-4-methoxy-phenyl)-2-hydroxy-propyl]-amide

Scheme I, Step A: 2-(2-Fluoro-4-methoxy-phenyl)-2-hydroxy-propylaminehydrochloride was converted to the free base by partitioning betweenethyl acetate and 1 M NaOH. The amine (1.0 g, 5.02 mmol) was combinedwith propane-2-sulfonic acid benzotriazol-1-yl ester (1.3 g, 5.52 mmol)in DMF (25 mL) and heated at 120° C. for 2 hr. then cooled to roomtemperature. The reaction mixture was diluted with ethyl acetate andextracted with 1 M HCl. The organic layer was separated and washed withwater and saturated NaCl, dried (MgSO₄), filtered, and concentrated to ayellow oil which was used in the next step without purification.

Preparation of Final Title Compound

Scheme I, Step B: A dry CH₂Cl₂ solution (10 mL) of (diethylamino)sulfurtrifluoride (DAST) (0.419 mL, 3.17 mmol) was cooled to −78° C. whilestirring under N₂. A CH₂Cl₂ solution (5 mL) of propane-2-sulfonic acid[2-(2-fluoro-4-methoxyphenyl)-2-hydroxy-propyl]-amide (0.79 g, 2.64mmol) was added dropwise via syringe and the reaction was immediatelybrought to 0° C. The reaction was quenched with water and diluted withdiethyl ether. The organic layer was separated and washed with water andsaturated NaCl solution, dried (MgSO₄), filtered, and concentrated to ayellow oil. The crude residue was purified by silica gel chromatography,eluting with 30% ethyl acetate/hexanes, to provide the final titlecompound, propane-2-sulfonic acid[2-fluoro-2-(2-fluoro-4-methoxy-phenyl)-propyl]-amide, (0.52 g, 64%) asa light yellow oil.

¹HNMR (CDCl₃) δ 1.20–1.22 (6H, d), 1.24–1.26 (6H, d), 1.68–1.73 (1H, d),3.25 (1H, sept), 3.58–3.66 (2H, m), 3.80 (3H, s), 4.20 (1H, t), 6.60(1H, m), 6.73 (1H, m), 7.36 (1H, t).

The following Table I specifically illustrates additional preferredsubstituents for R¹ Table I.

R¹

The following Table II illustrates additional compounds of the presentinvention. The following compounds can be prepared by one of ordinaryskill in the art in a manner analogous to the techniques and proceduresdescribed hereinabove. The starting materials and reagents are readilyavailable to one of ordinary skill in the art.

TABLE II Example Compound 54

55

56

57

58

1. A compound of the formula:

wherein: A represents SO₂; R^(a) represents (1–6C)alkyl, (2–6C)alkenyl,—(1–4C)alkyl(3–8C)cycloalkyl, or —(1–4C)alkylaromatic: R^(b) representsH, (1–6C)alkyl, (2–6C)alkenyl, —(1–4C)alkyl(3–8C)cycloalkyl, or—(1–4C)alkylaromatic; or R^(a) and R^(b) together with the carbon atomsto which they are attached form a (3–8C) saturated carbocyclic ring, a(3–8C) saturated carbocyclic ring containing a heteroatom selected fromthe group consisting of sulfur or oxygen, or a (5–8C) carbocyclic ringcontaining one double bond; R¹ represents an unsubstituted orsubstituted aromatic group, an unsubstituted or substitutedheteroaromatic group, or an unsubstituted or substituted(5–8C)cycloalkyl group; R²represents (1–6C)alkyl, (3–6C)cycloalkyl,(1–6C)fluoroalkyl, (1–6C)chloroalkyl, (2–6C)alkenyl,(1–4C)alkoxy(1–4C)alkyl, phenyl which is unsubstituted or substituted byhalogen, (1–4C)alkyl or (1–4C)alkoxy, or when A represents SO₂, a groupof formula R³R⁴N in which R³ and R⁴ each independently represents(1–4C)alkyl or, together with the nitrogen atom to which they areattached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino,piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein R¹ represents a naphthyl group or a phenyl, furyl,thienyl or pyridyl group which is unsubstituted or substituted by one ortwo substituents selected independently from halogen; nitro; cyano;hydroxyimino; (1–10C)alkyl; (2–10C)alkenyl; (2–10C)alkynyl;(3–8C)cycloalkyl; hydroxy(3–8C)cycloalkyl; oxo(3–8C)cycloalkyl;halo(1–10C)alkyl; (CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1to 4, X¹ represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOOor OCONR¹³, R⁹ represents hydrogen, (1–10C)alkyl, (3–10C)alkenyl,(3–10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or(3–8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently representshydrogen or (1–10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together withthe nitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl or morpholino group; N-(1–4C)alkylpiperazinyl;N-phenyl(1–4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1–4)alkoxycarbonyldihydrothiazolyl;(1–4C)alkoxycarbonyldimethyldihydro-thiazolyl; tetrahydro-thienyl;tetrahydrofuryl; tetrahydrothiopyranyl: tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH orCH═CH, L^(a) and L^(b) each represent (1–4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen,nitro, cyano, hydroxyimino, (1–10C) alkyl, (2–10C)alkenyl,(2–10C)alkynyl, (3–8C)cycloalkyl, 4-(1,1-dioxotetrahydro-1,2-thiazinyl),halo(1–10C)alkyl, cyano(2–10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, NHCONH,OCONR¹⁹ or NR¹⁹COO, R¹⁵ represents hydrogen, (1–10C)alkyl,phenyl(1–4C)alkyl, halo(1–10C)alkyl, (1–4C)alkoxycarbonyl(1–4C)alkyl,(1–4C)alkylsulfonylamino(1–4C)alkyl,(N-(1–4C)alkoxycarbonyl)(1–4C)alkylsulfonylamino-(1–4C)alkyl,(3–10C)alkenyl, (3–10C)alkynyl, (3–8C)-cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1–4C)alkyl, halo(1–4C)alkyl,di(1–4C)alkylamino and (1–4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1–10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 3. Acompound according to claim 2 wherein R² represents (1–6C)alkyl,(3–6C)cycloalkyl, fluoro(1–6C)alkyl, chloro(1–6C)alkyl, (2–6C)alkenyl1–4C)alkoxy(1–4C)alkyl, heteroaromatic, or phenyl which is unsubstitutedor substituted by halogen, (1–4C)alkyl or (1–4C)alkoxy.
 4. A compoundaccording to claim 3 wherein R² represents (1–6C)alkyl, (3–6C)cycloalkylor heteroaromatic, or phenyl which is unsubstituted or substituted byhalogen, (1–4C)alkyl or (1–4C)alkoxy.
 5. A compound according to claim 4wherein R² represents methyl, ethyl, isopropyl, t-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, isovaleryl, phenyl, benzyl,2-furyl, 2-thienyl, 5-oxazoyl, 2-pyridyl, 3-pyridyl, or 4-pryidyl.
 6. Acompound according to claim 5 wherein R^(a) represents (1–6C)alkyl or(2–6C)alkenyl.
 7. A compound according to claim 6 wherein R^(a)represents methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, pentylor hexyl.
 8. A compound according to claim 7 wherein R^(a) representsmethyl.
 9. A compound according to claim 8 wherein R^(b) represents H,(1–6C)alkyl, or (2–6C)alkenyl.
 10. A compound according to claim 8wherein R^(b) represents H.
 11. A compound according to claim 8 whereinR¹ is selected from the group consisting of


12. A compound selected from the group consisting of:[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine;[2-fluoro-2-(4-phenylphenyl)propyl][(methylethyl)sulfonyl]amine;4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenecarbonitrile;4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid;{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine;[2-fluoro-2-(40{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine;[2-fluoro-2-(4-(3-thienyl)phenyl)propyl][(methylethyl)sulfonyl]amine;[2-fluoro-2-(4-3-pyridyl)phenyl)propyl][(methylethyl)sulfonyl]amine;2-{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}ethanenitrile;4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzaldehyde;{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide;{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N,N-dimethylcarboxamide;N-ethyl{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}carboxamide;4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenylpyrrolidinyl ketone;N-{3-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}acetamide;N-{3-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}propanamide;N-{3-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}butanamide;amino-N-{3-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}amide;N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzamide;(3-cyanophenyl)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide;N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-4-pyridylcarboxamide;N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]{4-[2(methoxycarbonylamino)ethyl]phenyl}carboxamide;(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-fluoropropyl)[(methylethyl)sulfonyl]amine;{2-fluoro-2-[4-(4-{2[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine;(4-chlorophenyl)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide;(6-chloro(3-pyridyl))-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide;(4-cyanophenyl)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide;ethoxy-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carboxamide;N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]isoxazol-5-ylcarboxamide;4-(dimethylamino)-N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]butanamide;N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]-3-thienylcarboxamide;{2-fluoro-2-[4-(phenylmethoxy)phenyl]propyl}[(methylethyl)sulfonyl]amine;2-{[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenoxy]methyl}benzenecarbonitrile;[2-fluoro-2-(4-methoxyphenyl)propyl][(methylethyl)sulfonyl]amine;{2-[4-(3,5-difluorophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine;[(dimethylamino)sulfonyl][2-fluoro-2-(4-iodophenyl)propyl]amine;4-[4-(2-{[(dimethylamino)sulfonyl]amino}-1-fluoro-isopropyl)phenyl]benzenecarbonitrile;{2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine;[(dimethylamino)sulfonyl][2-fluoro-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl]amine;[(dimethylamino)sulfonyl]{2-fluoro-2-[4-(3-{[(methylethyl)sulfonyl]amino}phenyl)phenyl]propyl}amine;4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenesulfonamide;N-(2-{3-fluoro-4′-[1-fluoro-1-methyl-2-(propane-2sulfonylamino)-ethyl]biphenyl-4-yl}-ethyl)-isobutyramide;N-(2-{3-fluoro-4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-yl}-ethyl)-acetamide;N-{2-(2-fluoro-2-[3′-fluoro-4′-(2-methanesulfonylamino)-ethyl)-biphenyl-4-yl]propyl}-2-propanesulfonamide;N-{2-(2-fluoro-2-[3′-fluoro-4′-(2-(propane-2-sulfonylamino)-ethyl)-biphenyl-4-yl]propyl}-2-propanesulfonamide;N-(2-{3′-fluoro-4′-[2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-yl}-2-hydroxypropyl)-2-propanesulfonamide;N-{2-Fluoro-2-[4-(2-oxo-2,3-dihydro-1H-indol-6-yl)-phenyl]-propyl}-2-propanesulfonamide;(+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine;(−)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine;[2-fluoro-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine(enantiomer 1);[2-fluoro-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine(enantiomer 2);{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide(enantiomer 1); and{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide(enantiomer 2); and the pharmaceutically acceptable salts thereof.
 13. Acompound of the formula:

wherein R¹ represents an unsubstituted or substituted aromatic group, anunsubstituted or substituted heteroaromatic group, or an unsubstitutedor substituted (5–8C)cycloalkyl group; or a pharmaceutically acceptablesalt thereof.
 14. A compound according to claim 13 wherein R¹ representsa substituted aromatic group.
 15. A compound according to claim 14wherein the substituted aromatic group is a substituted phenyl.
 16. Acompound according to claim 15, wherein the substituted phenyl issubstituted with halogen; nitro; cyano; hydroxyimino; (1–10C) alkyl;(2–10C)alkenyl; (2–10C)alkynyl; (3–8C)cycloalkyl;hydroxy(3–8C)cycloalkyl; oxo(3–8C)cycloalkyl; halo(1–10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO, OCONR¹³,R⁹ represents hydrogen, (1–10C) alkyl, (3–10C)alkenyl, (3–10C)alkynyl,pyrrolidinyl, tetrahydrofuryl, morpholino or (3–8C)cycloalkyl and R¹⁰,R¹¹, R¹² and R¹³ each independently represents hydrogen or (1–10C)alkyl,or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogen atom to whichthey are attached from an azetidinyl, pyrrolidinyl, piperidinyl ormorpholino group; N-(1–4C)alkylpiperazinyl;N-phenyl(1–4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1–4C)alkoxycarbonyl dihydrothiazolyl;(1–4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1–4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1–10C) alkyl; (2–10C)alkenyl; (2–10C)alkynyl;(3–8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1–10C)alkyl; cyano(2–10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(CH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ orNR¹⁹COO, R¹⁵ represents hydrogen, (1–10C)alkyl, phenyl(1–4C)alkyl,halo(1–10C)alkyl, (1–4C)alkoxycarbonyl(1–4C)alkyl,(1–4C)alkylsulfonylamino(1–4C)alkyl,N-(1–4C)alkoxycarbonyl)(1–4C)alkylsulfonylamino(1–4C)alkyl,(3–10C)alkenyl, (3–10C)alkynyl, (3–8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1–4C)alkyl, halo(1–4C)alkyl,di(1–4C)alkylamino and (1–4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1–10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 17. Acompound according to claim 16 wherein the substituted phenyl issubstituted with a group of formula R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) inwhich X² represents a bond, O, NH, S, SO, SO₂, CO, CH(OH), CONH, NHCO,NHCONH, NHCOO, COCONH, OCH₂CONH, or CH═CH, L^(a) and L^(b) eachrepresent (1–4C)alkylene, one of n and m is 0 or 1 and the other is 0,and R¹⁴ represents a phenyl or heteroaromatic group which isunsubstituted or substituted by one or two of halogen; nitro; cyano;(1–10C) alkyl; (2–10C)alkenyl; (2–10C)alkynyl; (3–8C)cycloalkyl;4-(1,1-dioxotetrahydro-1,2-thiazinyl; halo(1–10C)alkyl;cyano(2–10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ in which z is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ or NR¹⁹COO, R¹⁵represents hydrogen, (1–10C)alkyl, phenyl(1–4C)alkyl, halo(1–10C)alkyl,(1–4C)alkoxycarbonyl(1–4C)alkyl, (1–4C)alkylsulfonylamino(1–4C)alkyl,N-(1–4C)alkoxycarbonyl)(1–4)alkylsulfonylamino(1–4C)alkyl,(3–10C)alkenyl, (3–10C)alkynyl, (3–8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1–4C)alkyl, halo(1–4C)alkyl,di(1–4C)alkylamino and (1–4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1–10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 18. Acompound according to claim 17 wherein (L^(a))_(n)—X²—(L^(b))_(m)represents a bond, CONH, or CH₂O.
 19. A compound according to claim 18wherein R¹⁴ represents a phenyl which is unsubstituted or substituted byone or two of halogen; nitro; cyano; (1–10C) alkyl; (2–10C)alkenyl;(2–10C)alkynyl; (3–8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1–10C)alkyl; cyano(2–10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ orNR¹⁹COO, R¹⁵ represents hydrogen, (1–10C)alkyl, phenyl(1–4C)alkyl,halo(1–10C)alkyl, (1–4C)alkoxycarbonyl(1–4C)alkyl,(1–4C)alkylsulfonylamino(1–4C)alkyl,N-(1–4C)alkoxycarbonyl)(1–4C)alkylsulfonylamino(1–4C)alkyl,(3–10C)alkenyl, (3–10C)alkynyl, (3–8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1–4C)alkyl, halo(1–4C)alkyl,di(1–4C)alkylamino and (1–4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represent hydrogen or (1–10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 20. Acompound according to claim 18 wherein phenyl is substituted by one ortwo of halogen; nitro; cyano; (1–10C) alkyl; halo(1–10C)alkyl; and(CH₂)_(z)X³R¹⁵ in which z is 0, 1 or 2, X³ represents O, NR¹⁶, CO, COO,CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂R¹⁷, OCONR¹⁹ or NR¹⁹COO, R¹⁵represents hydrogen, (1–10C)alkyl, phenyl(1–4C)alkyl, halo(1–10C)alkyl,or (3–10C)alkenyl, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ each independentlyrepresent hydrogen or (1–10C)alkyl.
 21. A compound according to claim 18wherein phenyl is substituted by one or two of fluoro; chloro, cyano;(1–4C)alkyl; trifluoromethyl; and (CH₂)_(z)X³R¹⁵ in which z is 0, or 2,X³ represents NR¹⁶, CO, COO, CONR¹⁷, NR¹⁸CO, NHSO₂, R¹⁵ representshydrogen, (1–4C)alkyl, phenyl(1–4C)alkyl, or halo(1–4C)alkyl, and R¹⁶,R¹⁷, R¹⁸ and R¹⁹ each independently represents hydrogen or (1–4C)alkyl.22. A compound according to claim 18 wherein phenyl is substituted byone of fluoro; chloro; cyano; (1–4C)alkyl; trifluoromethyl; and(CH₂)_(z)X³R¹⁵ in which z is 0, or 2, X³ represents NR¹⁶, CO, COO,CONR¹⁷, NR¹⁸CO, NHSO₂, R¹⁵ represents hydrogen, (1–4C)alkyl,phenyl(1–4C)alkyl, or halo(1–4C)alkyl, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represent hydrogen or (1–4C)alkyl.
 23. A compound of theformula:

or a pharmaceutically acceptable salt thereof, wherein R^(a) represents(1–6C)alkyl, (2–6C)alkenyl, —(1–4C)alkyl(3–8C)cycloalkyl, or—(1–4C)alkylaromatic; R^(b) represents H, (1–6C)alkyl, (2–6C)alkenyl,—(1–4C)alkyl(3–8C)cycloalkyl, or —(1–4C)alkylaromatic; or R^(a) andR^(b) together with the carbon atoms to which they attached form a(3–8C) saturated carbocyclic ring, a (3–8C) saturated carbocyclic ringcontaining a heteroatom selected from the group consisting of sulfur oroxygen, or a (5–8C) carbocyclic ring containing one double bond; and R¹is selected from the group consisting of:


24. A pharmaceutical composition, which comprises a compound as claimedin claim 1 and a pharmaceutically acceptable diluent or carrier.
 25. Acompound which is selected from the group consisting of:{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide;and{4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}-N-methylcarboxamide(enantiomer 1); and the pharmaceutically acceptable salts thereof.